supplementary appendix - thelancet.com homepage appendix ... arti bhan (i); terra cushman (c ......

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Beck RW, Riddlesworth TD, Ruedy KJ, et al, for the DIAMOND Study Group. Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol 2017; published online July 12. http://dx.doi.org/10.1016/S2213-8587(17)30217-6.

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Online Supplemental Materials

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Participating Clinical Sites

Personnel are listed as (I) for Study Investigator and (C) for Study Coordinator. Sites are listed

in order by number of subjects randomized into the study. The number of subjects randomized is

noted in parentheses preceded by the site location and site name.

Joslin Diabetes Center, Boston, MA (13): Elena Toschi (I); Howard Wolpert (I); Astrid Atakov-

Castillo (C); Edvina Markovic (C); Research Institute of Dallas, Dallas, TX (8): Stephen Aronoff

(I); Satanya Brooks (C); Gloria Martinez (C); Angela Mendez (C); Theresa Dunnam (C); Iowa

Diabetes & Endocrinology Research Center, Des Moines, IA (8): Anuj Bhargava (I); Kathy

Fitzgerald (I); Diana Wright (I); Teck Khoo (I); Pierre Theuma (I); Tara Herrold (C); Debra

Thomsen (C); Park Nicollet Institute - International Diabetes Center, St. Louis Park, MN (6):

Richard Bergenstal (I); Kathleen McCann (C); Arlene Monk (C), Char Ashanti (C); Rocky

Mountain Diabetes and Osteoporosis Center, Idaho Falls, ID (6): David Liljenquist (I); Heather

Judge (C); Jean Halford (C); Henry Ford Medical Center Division of Endocrinology, Detroit,

MI (5): Davida Kruger (I); Shiri Levy (I); Arti Bhan (I); Terra Cushman (C); Lameka Dawson

(C); Heather Remtema (C); Portland Diabetes & Endocrinology Center, Portland, OR (4): Fawn

Wolf (I); James Neifing (I); Jennifer Murdoch (I); Susan Staat (C); Tamara Mayfield (C);

Oregon Health & Science University, Portland, OR (4): Andrew Ahmann (I); Bethany

Klopfenstein (I); Farahnaz Joarder (I); Kathy Hanavan (I); Jessica Castle (I); Diana Aby-Daniel

(I); Victoria Morimoto (I); Donald DeFrang (C); Bethany Wollam (C); Washington University

in St. Louis, St. Louis, MO (3): Janet McGill (I); Olivia Jordan (C); Carol Recklein (C);

Diabetes & Glandular Disease Clinic, San Antonio, TX (2): Mark Kipnes (I); Stacie Haller (C);

Terri Ryan (C); Atlanta Diabetes Associates, Atlanta, GA (2): Bruce Bode (I); Jennifer Boyd (I);

Nitin Rastogi (C); Katherine Lindmark (C); Amarillo Medical Specialists LLP, Amarillo, TX

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(2): William Biggs (I); Lorena Sandoval (C); Robin Eifert (C); Becky Cota (C); Accent Clinical

Trials, Las Vegas, NV (2): Quang Nguyen (I); Alejandra Martinez (C); Cathy Duran (C); East

Coast Institute for Research, LLC, Jacksonville, FL (2): Scott Segel (I); David Sutton (I); Miguel

Roura (I); Rebecca Rosenwasser (C); Jennifer McElveen (C); Emily Knisely (C); Anne Johnson

(C); Physicians Research Associates, LLC, Lawrenceville, GA (2): A. Ola Odugbesan (I); Karla

Wardell (C); Carolyn Paulus (C); Advanced Research Institute, Ogden, UT (2): Jack Wahlen (I);

Jon Winkfield (I); Hilary Wahlen (C); Emily Hepworth (C); David Winkfield (C); Sue Owens

(C); Columbus Regional Research Institute, Columbus, GA (1): Steven Leichter (I); Emily

Evans (C); Diabetes & Endocrine Associates PC, Omaha, NE (1): Sarah Konigsberg (I);

Jennifer Rahman (C); Marin Endocrine Care & Research Inc., Greenbrae, CA (1): Linda

Gaudiani (I); Natalie Woods (C); Jesse Cardozo (C); Laureate Medical Group at Northside, LLC,

Atlanta, GA (1): Kate Wheeler (I); Jennifer Kane (C); Terri Eubanks (C)

Coordinating Center

Jaeb Center for Health Research, Tampa, FL: Katrina Ruedy; Roy W. Beck; Craig Kollman;

Tonya Riddlesworth, Thomas Mouse

Sponsor

Dexcom, Inc., San Diego, CA: David Price; Eileen Casal; Claudia Graham

Quality of Life Collaborator

University of California, San Diego, La Jolla, CA: William Polonsky

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Supplemental Figure 1. Eligibility Flowchart

Randomized to Phase 1 CGM Group

N=105

Completed Phase 1 Week 24 Visit

N=102

* 1 participant erroneously randomized (using 101 units of insulin per day)

Not continuing on to Phase 2 (n=27)

10 were using >100 units of insulin per day

2 had insufficient CGM usage in the prior 28 days

14 were eligible but declined to continue

Dropped from study (n=3)

1 lost to follow up

1 site withdrew participant

Randomized to Phase 2

N=75 *

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Supplemental Table 1. CGM Outcomes at Weeks 14 and 28

A. 14 Weeks Baseline * Week 14*

Adjusted Mean Difference

(99% Confidence Interval) CGM+CSII

(N=37)

CGM+MDI

(N=38)

CGM+CSII

(N=35)

CGM+MDI

(N=35)

Hours of Data median (quartiles) 628 (576, 648) 637 (618, 655) 636 (618, 650) 637 (602, 651)

Minutes/Day in Range 70-180

mg/dL (3·9-10·0 mmol/L) mean ±

SD

708 ± 162 762 ± 224 792 ± 161 732 ± 235 +83 (-14, +181)

Mean Glucose mean ± SD mg/dL

(mmol/L)

185 ± 24

(10·3±1·3)

178 ± 31

(9·9±17·2)

172 ± 22

(9·5±1·2)

183 ± 36

(10·2±2·0)

-14 (-28, +28)

(-0·8 (-1·6, +1·6)

Hyperglycemia median (quartiles)

Minutes/day >180 mg/dL

(>10·0 mmol/L) 661 (557, 836) 601 (467, 793) 575 (462, 724) 688 (483, 828)


(>13·9 mmol/L) 260 (176, 371) 220 (105, 309) 169 (128, 260) 216 (121, 346)


(>16·6 mmol/L) 110 (56, 165) 61 (25, 104) 61 (22, 81) 64 (38, 114)

Area under curve 180 mg/dL

(10·0 mmol/L) 32 (22, 42) 25 (14, 36) 22 (17, 31) 26 (17, 38)

Hypoglycemia median (quartiles)

Minutes/day <70 mg/dL (3·9

mmol/L) 34 (25, 58) 41 (23, 75) 44 (29, 89) 34 (12, 61)


mmol/L) 14 (9, 27) 16 (11, 30) 21 (10, 43) 13 (4, 27)


mmol/L) 4 (2, 10) 4 (2, 12) 8 (2, 20) 4 (0, 9)

Area above curve 70 mg/dL (3·9

mmol/L) 0·25 (0·17, 0·45) 0·28 (0·18, 0·50) 0·39 (0·19, 0·76) 0·22 (0·07, 0·45)

Coefficient of Variation median

(quartiles) 39% (37%, 42%) 37% (35%, 42%) 38% (36%, 42%) 36% (33%, 39%)

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B. 28 Weeks Baseline * Week 28*



(N=37)

CGM+MDI

(N=38)

CGM+CSII

(N=34)

CGM+MDI

(N=35)


Minutes/Day in Range 70-180

mg/dL (3·9-10·0 mmol/L) mean ±

SD

708 ± 162 762 ± 224 795 ± 182 746 ± 223 +72 (-36, +181)


(mmol/L)

185 ± 24

(10·3±1·3)

178 ± 31

(9·9±17·2)

172 ± 25

(9·5±1·4)

180 ± 32

(10·0±1·8)

-11 (-26, +4)

(-0·6 (-1·4, +0·2))



(>10·0 mmol/L) 661 (557, 836) 601 (467, 793) 581 (472, 717) 684 (482, 826)


(>13·9 mmol/L) 260 (176, 371) 220 (105, 309) 175 (114, 299) 197 (120, 298)


(>16·6 mmol/L) 110 (56, 165) 61 (25, 104) 58 (31, 111) 76 (28, 104)

Area under curve 180 mg/dL

(10·0 mmol/L) 32 (22, 42) 25 (14, 36) 22 (15, 35) 26 (17, 34)



mmol/L) 34 (25, 58) 41 (23, 75) 47 (32, 73) 27 (11, 56)


mmol/L) 14 (9, 27) 16 (11, 30) 22 (13, 38) 14 (4, 26)


mmol/L) 4 (2, 10) 4 (2, 12) 8 (4, 13) 4 (1, 9)


mmol/L) 0·25 (0·17, 0·45) 0·28 (0·18, 0·50) 0·37 (0·23, 0·61) 0·26 (0·07, 0·44)


(quartiles) 39% (37%, 42%) 37% (35%, 42%) 38% (37%, 42%) 36% (33%, 40%)

* Baseline refers to time of randomization for this trial (phase 2 of the study). 14-week results exclude 1 participant in the CGM+MDI Group and 28-week results

exclude 2 participants in the CGM+CSII Group with <72 hours of data in the 28 days prior to the visit. Treatment group comparisons are based on linear regression models

adjusted for the baseline value, baseline HbA1c, and clinical site as a random effect.

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Supplemental Table 2. Per-protocol Analyses

Baseline* Pooled Follow-up * Adjusted Mean Difference

(95% Confidence Interval) †

P value † CGM+CSII CGM+MDI CGM+CSII CGM+MDI

Primary Analysis

N 37 38 36 36

Minutes/Day in Range 70-180 mg/dL

(3·9-10·0 mmol/L) mean ± SD 708 ± 162 762 ± 224 791 ± 157 741 ± 225 +83 (+17, +149) 0·01

Per-protocol Analysis #1

N 33 32 33 32


(3·9-10·0 mmol/L) mean ± SD 729 ± 158 767 ± 225 798 ± 158 747 ± 222 +75 (+3, +148) 0·04

Per Protocol Analysis #2

N 36 32 36 32


(3·9-10·0 mmol/L) mean ± SD 713 ± 161 748 ± 233 791 ± 157 723 ± 228 +93 (+24, +162) 0·01

* Baseline refers to phase 2 randomization. Pooled follow up combines all post-phase 2 randomization data after the first 4 weeks.

† Treatment group comparisons based on linear regression models adjusted for baseline time in range, baseline HbA1c, and clinical site as a random effect. Primary analysis excluded 1 CGM+CSII and 2 CGM+MDI participants with <72 hours of follow-up data (none of whom completed the study).

Per-protocol analysis #1 inclusion criteria: completion of the 28-week exam within the window of ±30 days, CGM usage averaging a minimum of 6 days per week,

insulin pump being used at the time of the 28-week visit (CGM+CSII Group), and insulin pump not used at any time during the trial (CGM+MDI Group); excluded

4 in the CGM+CSII Group and 6 in the CGM+MDI Group

Per-protocol analysis #2 excluded participants who started an oral glucose lowering agent post-randomization, initiated CSII if assigned to the CGM+MDI Group, or

had <72 hours of follow-up data; excluded 1 in the CGM+CSII Group and 6 in the CGM+MDI Group

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Supplemental Table 3. Daytime CGM Metrics Using Pooled Data (6am to <10pm)

* Baseline refers to phase 2 randomization. Pooled Follow Up combinesall post-phase 2 randomization data after the first 4 weeks. Excludes 1 CGM+CSII and 2

CGM+MDI participants with <72 hours of follow-up data (none of whom completed the study). Treatment group comparisons are based on linear regression

models adjusted for the baseline value, baseline HbA1c, and clinical site as a random effect.

Baseline* Pooled Follow-up *



(N=37)

CGM+MDI

(N=38)

CGM+CSII

(N=36)

CGM+MDI

(N=36)


% Time in Range 70-180 mg/dL (3·9-

10·0 mmol/L) mean ± SD 51% ± 12% 53% ± 16% 58% ± 11% 51% ± 15%

Change in % Time in Range from

Phase 2 Baseline mean ± SD NA NA +7% ± 14% -2% ± 8% +8% (+2%, +15%)


(mmol/L) 182 ± 25 (10·1±1·4) 178 ± 31 (9·9±1·7) 166 ± 23 (9·2±1·3) 182 ± 33 (10·1±1·8)

-18 (-31, -5)

(-1·0 (-1·7, -0·3))


Minutes/day >180 mg/dL (>10·0

mmol/L) 45% (36%, 56%) 43% (31%, 52%) 38% (27%, 46%) 45% (35%, 57%)


mmol/L) 17% (13%, 25%) 14% (8%, 22%) 10% (7%, 16%) 15% (8%, 23%)


mmol/L) 7% (4%, 10%) 4% (2%, 9%) 4% (2%, 6%) 4% (3%, 8%)

Area under curve 180 mg/dL (10·0

mmol/L) 29 (22, 40) 26 (15, 36) 20 (14, 27) 27 (18, 38)


Minutes/day <70 mg/dL (<3·9

mmol/L) 2·4% (1·7%, 3·7%) 2·6% (1·3%, 5·3%) 3·3% (2·6%, 6·3%) 2·1% (1·0%, 3·4%)


mmol/L) 0·9% (0·6%, 1·7%) 1·0% (0·5%, 1·7%) 1·4% (1·0%, 3·2%) 0·8% (0·4%, 1·4%)


mmol/L) 0·2% (0·1%, 0·6%) 0·3% (0·1%, 0·8%) 0·5% (0·3%, 1.2%) 0·2% (0·1%, 0·6%)


mmol/L) 0·22 (0·14, 0·43) 0·27 (0·12, 0·51) 0·36 (0·26, 0·80) 0·21 (0·10, 0·38)


(quartiles) 39% (37%, 43%) 38% (35%, 41%) 39% (37%, 42%) 37% (33%, 39%)

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Supplemental Table 4. Nighttime CGM Metrics Using Pooled Data (10pm to <6am)

Baseline* Pooled Follow-up *



(N=37)

CGM+MDI

(N=38)

CGM+CSII

(N=36)

CGM+MDI

(N=36)


% Time in Range 70-180 mg/dL (3·9-10·0

mmol/L) mean ± SD 46% ± 14% 52% ± 18% 48% ± 12% 52% ± 18%

Change in % Time in Range from Phase 2

Baseline mean ± SD NA NA +2% ± 14% 0% ± 9% 0% (-8%, 7%)


(mmol/L)

189 ± 30

(10·5±1·7) 177 ± 35 (9·8±1·9) 184 ± 25 (10·2±1·4) 181 ± 37 (10·0±2·1)

-3 (-17, +11)

(-0·2 (-0·9, +0·6))



mmol/L) 48% (38%, 63%) 42% (31%, 54%) 47% (40%, 59%) 44% (30%, 57%)


mmol/L) 20% (11%, 31%) 13% (6%, 22%) 15% (11%, 25%) 14% (8%, 22%)


mmol/L) 8% (4%, 13%) 4% (2%, 8%) 5% (3%, 9%) 4% (3%, 8%)

Area under curve 180 mg/dL (10·0

mmol/L) 32 (23, 49) 22 (14, 38) 27 (21, 40) 26 (16, 36)


Minutes/day <70 mg/dL (<3·9 mmol/L) 2·8% (1·5%, 4·7%) 3·5% (1·5%, 5·7%) 2·9% (1·3%, 5·1%) 2·1% (1·0%, 4·7%)




mmol/L) 0·29 (0·16, 0·43) 0·34 (0·12, 0·61) 0·34 (0·18, 0·60) 0·24 (0·10, 0·54)

Coefficient of Variation median (quartiles) 39% (35%, 43%) 36% (32%, 42%) 38% (35%, 40%) 36% (34%, 40%)

* Baseline refers to phase 2 randomization. Pooled Follow Up combines all post-phase 2 randomization data after the first 4 weeks. Excludes 1 CGM+CSII and

2 CGM+MDI participants with <72 hours of follow-up data (none of whom completed the study). Treatment group comparisons are based on linear regression

models adjusted for the baseline value, baseline HbA1c, and clinical site as a random effect.

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Supplemental Table 5. Change in Time <70 mg/dL (<3·9 mmol/L) According to Baseline Subgroups

Change in % Time <70 mg/dL (<3·9 mmol/L)

from Baseline * P value for

interaction || CGM+CSII CGM+MDI

Phase 2 Baseline Factor N median (quartiles)

N

median (quartiles)

Time in Range 70-180 mg/dL

(3·9-10·0 mmol/L) 0·02

<53% 20 +1·1% (0·0%, +2·9%) 19 -0·5% (-0·8%, +0·4%)

≥53% 16 +0·1% (-1·6%, +1·6%) 17 -0·4% (-0·9%, +0·1%)

Time<70 mg/dL (<3·9 mmol/L) 0·04

<3% 25 +1·0% (-0·0%, +1·9%) 19 +0·1% (-0·5%, +0·4%)

≥3% 11 -1·3% (-2·5%, +4·9%) 17 -0·9% (-1·4%, -0·7%)

HbA1c 0·0001

<7.5% (<58 mmol/mol) 14 -1·3% (-2·0%, +0·6%) 17 -0·4% (-1·1%, +0·1%)

≥7.5% (≥58 mmol/mol) 22 +1·3% (+0·4%, +3·7%) 19 -0·5% (-0·8%, +0·4%)

Age 0·28

<50 years 20 +1·3% (-0·1%, +2·4%) 21 -0·5% (-0·9%, +0·2%)

≥50 years 16 +0·4% (-1·6%, +1·1%) 15 -0·4% (-1·1%, +0·1%)

Blood Glucose Meter Testing † 0·80

<3 times/day 11 +0·9% (-0·1%, +2·2%) 16 -0·5% (-1·1%, +0·8%)

3-<5 times/day 15 +0·2% (-1·3%, +1·9%) 13 -0·8% (-1·1%, +0·1%)

≥5 times/day 8 +0·3% (-1·7%, +1·3%) 7 -0·5% (-0·5%, +0·4%)

Education † 0·55

<Bachelor degree 15 +0·7% (-0·3%, +2·7%) 15 -0·6% (-1·4%, +0·1%)

≥Bachelor degree 19 +1·0% (-1·3%, +1·9%) 19 -0·2% (-0·8%, +0·2%)

Clarke Hypoglycemia

Unawareness Score †, ‡ 0·54

Reduced Awareness or

Uncertain (Score ≥3) 13 +0·6% (-0·3%, +1·2%) 14 -0·7% (-0·9%, +0·2%)

Aware (Score ≤2) 23 +1·0% (-1·3%, +2·7%) 22 -0·3% (-0·9%, +0·1%)

Hypoglycemia Fear Score § 0·66

≤13 21 +1·0% (-0·1%, +2·2%) 18 -0·6% (-0·9%, +0·1%)

≥14 15 -0·0% (-1·3%, +1·6%) 18 -0·3% (-0·9%, +0·4%)

Time of Day 0·07

Daytime (6am-10pm) 36 +0.9% (-0.2%, +2.8%) 36 -0.3% (-1.0%, +0.3%)

Nighttime (10pm-6am) 36 +0.1% (-1.7%, +2.0%) 36 -0.2% (-1.5%, +0.4%) * Using all post-phase 2 randomization data after the first 4 weeks. Excludes 1 CGM+CSII and 2 CGM+MDI participants with <72 hours of follow-up data (none of whom

completed the study).

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† Blood glucose meter testing missing for 2 CGM+CSII participants; education missing for 2 CGM+CSII participants and 2 CGM+MDI participants; Hypoglycemia

Unawareness score missing for 1 CGM+CSII participant.

‡ The Clarke Hypoglycemia Unawareness questionnaires has 8 items with a total score from 0 to 7. Higher score denotes more unawareness.

§ The Hypoglycemia Fear questionnaire contains 18 items on what the participant worries about related to their diabetes. Higher score denotes more fear.

|| Treatment group comparison for time of day made by including both the day and night time <70 mg/dL (<3·9 mmol/L) in a repeated measures model adjusted for baseline time

<70 mg/dL (<3·9 mmol/L), baseline HbA1c, and clinical site as a random effect All other treatment group comparisons made by including an interaction term in each linear

regression model adjusted for baseline time <70 mg/dL (<3·9 mmol/L), baseline HbA1c, and clinical site as a random effect. The model for the subgroup based on time in

range did not adjust for baseline time <70 mg/dL since time in range and time <70 mg/dL (<3·9 mmol/L) are highly correlated in this data (0·68). Continuous variable used for

all subgroup factors other than education. Due to a skewed distribution, the models are based on ranks using van der Waerden scores.

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Supplemental Table 6. HbA1c Outcomes

A. 14 Weeks Baseline *, † Week 14 †


(99% Confidence Interval) ‡ P value ‡ CGM

+CSII

(N=37)

CGM

+MDI

(N=38)

CGM

+CSII

(N=35)

CGM

+MDI

(N=36)

HbA1c - % (mmol/mol) mean ± SD 7·6 ± 0·7

(60±7·7)

7·6 ± 0·9

(60±9·8)

7·7 ± 0·6

(61±6·6)

7·6 ± 1·0

(60±10·9)

Change in HbA1c from Baseline - %

(mmol/mol) mean ± SD NA NA

+0·1 ± 0·9

(+1·1±9·8)

0·0 ± 0·5

(0±5·5)

+0·1 (-0·4, +0·5)

(+1·1 (-4·4, +5·5) 0·67

HbA1c < 7.0% (<53 mmol/mol) n (%) 6 (16%) 9 (24%) 3 (9%) 9 (25%) -13% (-33%, +8%) 0·34

HbA1c < 7.5% (<58 mmol/mol) n (%) 14 (48%) 18 (47%) 12 (34%) 19 (53%) -16% (-52%, +19%) 0·13

Relative Reduction in HbA1c ≥10% n (%) NA NA 4 (11%) 1 (3%) +10% (-5%, +27%) 0·36

Reduction in HbA1c ≥1% (≥10·9

mmol/mol) n (%) NA NA 3 (9%) 1 (3%) +8% (-6%, +22%) 0·21

Reduction in HbA1c ≥1% (≥10·9

mmol/mol) OR HbA1c <7.0% (<53

mmol/mol) n (%)

NA NA 5 (14%) 10 (28%) -12% (-36%, +12%) 0·21

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B. 28 Weeks Baseline *, † Week 28


(99% Confidence Interval) ‡ P value ‡ CGM

+CSII

(N=37)

CGM

+MDI

(N=38)

CGM

+CSII

(N=36)

CGM

+MDI

(N=35)

HbA1c - % (mmol/mol) mean ± SD 7·6 ± 0·7

(60±7·7)

7·6 ± 0·9

(60±9·8)

7·9 ± 0·7

(63±7·7)

7·7 ± 1·0

(61±10·9)

Change in HbA1c from Baseline - %

(mmol/mol) mean ± SD NA NA

+0·3 ± 0·9

(+3·3±9·8)

+0·1 ± 0·4

(+1·1±4·4)

+0·2 (-0·3, +0·6)

(+2·2 (-3·3, +6·6) 0·32

HbA1c < 7.0% (<53 mmol/mol) n (%) 6 (16%) 9 (24%) 2 (6%) 9 (26%) -17% (-38%, +4%) 0·29

HbA1c < 7.5% (<58 mmol/mol) n (%) 14 (48%) 18 (47%) 12 (33%) 13 (37%) +1% (-30%, +31%) 0·93

Relative Reduction in HbA1c ≥10% n (%) NA NA 4 (11%) 1 (3%) +9% (-6%, +25%) 0·39

Reduction in HbA1c ≥1% (≥10·9 mmol/mol)

n (%) NA NA 3 (8%) 0 - -

Reduction in HbA1c ≥1% (≥10·9 mmol/mol)

OR HbA1c <7.0% (<53 mmol/mol) n (%) NA NA 4 (11%) 9 (26%) -13% (-37%, +9%) 0·39

* Baseline refers to time of randomization for this trial (phase 2 of the study).

† Due to missing central laboratory HbA1c, an imputed HbA1c value (based on the local laboratory value) was used for 1 CGM+CSII participant at baseline.

‡ Treatment group comparisons are based on linear regression models adjusted for baseline HbA1c and clinical site as a random effect.

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Supplemental Table 7. Insulin Use, Body Weight and Hypoglycemia Unawareness

Baseline * Week 28 † Adjusted Mean Difference

(99% Confidence Interval) || P value || CGM+CSII

(N=37)

CGM+MDI

(N=38)

CGM+CSII

(N=36)

CGM+MDI

(N=35)

# Boluses per Day mean ± SD 3·6 ± ·08 3·7 ± 1·1 4·3 ± 1·9 3·7 ± 1·0

0 0 0 1 (3%) 0

1 0 1 (3%) 0 0

2 0 0 3 (8%) 0

3 20 (54%) 20 (53%) 9 (25%) 18 (55%)

4 11 (30%) 10 (26%) 10 (28%) 9 (27%)

5 5 (14%) 4 (11%) 5 (14%) 4 (12%)

6 1 (3%) 2 (5%) 2 (6%) 1 (3%)

7 0 1 (3%) 3 (8%) 1 (3%)

8 0 0 3 (8%) 0

Change in # Boluses per Day from

Baseline mean ± SD +0·6 ± 1·9 0·0 ± 1·1 +0·5 (-0·5, +1·4) 0·17

-4 0 1 (3%)

-3 2 (6%) 0

-2 0 0

-1 8 (22%) 5 (15%)

0 9 (25%) 20 (61%)

+1 7 (19%) 6 (18%)

+2 5 (14%) 0

+3 1 (3%) 1 (3%)

+4 3 (8%) 0

+5 1 (3%) 0

< 0 19 (53%) 26 (79%) 0·27

≥ +1 17 (47%) 7 (21%)

Basal Units per Kg median (quartiles) 0·36

(0·25, 0·40)

0·31

(0·25, 0·39)

0·28

(0·21, 0·32)

0·31

(0·24, 0·38)

Change in Basal Units per Kg from

Baseline median (quartiles) NA NA

-0·07

(-0·12, -0·01)

+0·01

(0·00, +0·02)

Bolus Units per Kg median (quartiles) 0·37

(0·28, 0·45)

0·34

(0·25, 0·39)

0·22

(0·17, 0·30)

0·31

(0·26, 0·38)

Change in Bolus Units per Kg from

Baseline median (quartiles) NA NA

-0.12

(-0.17, -0.05)

+0·01

(-0·06, +0·04)

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Basal to Bolus Ratio median

(quartiles)

0·97

(0·75, 1·13)

1·06

(0·67, 1·47)

1·20

(0·75, 1·39)

1·08

(0·83, 1·30) 0·16

Total Daily Insulin Units per Kg

median (quartiles)

0·72

(0·50, 0·89)

0·67

(0·55, 0·77)

0·53

(0·40, 0·61)

0·61

(0·54, 0·73)

Change in Total Daily Insulin Units

per Kg from Baseline median

(quartiles)

NA NA -0·18

(-0·30, -0·08)

+0·01

(-0·04, +0·04) <0·0001

Weight (kg) mean ± SD ‡ 87 ± 14 83 ± 18 86 ± 14 83 ± 18

Change in Weight from Baseline (kg)

mean ± SD ‡ NA NA 0·0 ± 3·6 +0·6 ± 3·4 -0.7 (-3.0, +1.6) 0·42

Clarke Hypoglycemia Unawareness

Total Score mean ± SD ‡, § 2·1 ± 1·9 2·1 ± 1·9 2·0 ± 1·7 1·9 ± 1·7 +0·1 (-0·7, +0·9) 0·76

Reduced Awareness (Score 4 to ≤7) 9 (25%) 9 (24%) 10 (29%) 5 (14%)

Uncertain (Score = 3) 4 (11%) 5 (13%) 2 (6%) 8 (23%)

Aware (Score 0 to ≤2) 23 (64%) 24 (63%) 23 (66%) 22 (63%) * Baseline refers to time of randomization for this trial (phase 2 of the study).

† 2 CGM+MDI participants used a pump during follow-up and were excluded from the analysis of insulin data.

‡ Missing body weight for 1 CGM+CSII participant at 28 weeks; missing Hypoglycemia Unawareness score for 1 CGM+CSII subject at baseline and 1 CGM+CSII at 28

weeks.

§ The Clarke Hypoglycemia Unawareness questionnaires has 8 items with a total score from 0 to 7. Higher score denotes more unawareness.

|| Treatment group comparison for the binary outcome for the change in number of boluses per day is based on a logistic regression model adjusted for the baseline number of boluses

per day, baseline HbA1c, and clinical site as a random effect. All other treatment group comparisons are based on linear regression models adjusted for the corresponding baseline

value, baseline HbA1c, and clinical site as a random effect. The model for the change in weight also adjusted for age and sex. Due to skewed distributions, the models for basal to

bolus ratio and change in total daily insulin units per Kg are based on ranks using van der Waerden scores.

PROTOCOL

Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes:

DIaMonD Study

Protocol Number: PTL-901148

Study Sponsor: Dexcom, Inc.

6340 Sequence Drive

San Diego, CA 92121

Tel: (858) 200-0200

Fax: (858) 200-0201

Study Contact: Eileen Casal, RN, MSN

Senior Director, Clinical Affairs

Tel: (858) 875-9774

Fax: (858) 332-0192

Email: [email protected]

Version Date: 20 May 2015

Version Number: 03

CONFIDENTIAL

CONFIDENTIAL UNRELEASED

Protocol No. 901148

Version: 03

TABLE OF CONTENTS

1. ABBREVIATIONS AND DEFINITIONS ........................................................................................ i

2. INVESTIGATOR SIGNATURE SHEET ....................................................................................... iv

3. PROTOCOL SYNOPSIS .................................................................................................................. v

4. INTRODUCTION .............................................................................................................................. 1

5. STUDY OBJECTIVES ...................................................................................................................... 3

6. PRIMARY ENDPOINTS .................................................................................................................. 3

7. SECONDARY ENDPOINTS ............................................................................................................ 3

8. STUDY POPULATION .................................................................................................................... 4

9. STUDY ELIGIBILITY ..................................................................................................................... 4

9.1 Inclusion Criteria ............................................................................................................................... 4

9.2 Exclusion Criteria .............................................................................................................................. 4

10. STUDY DESIGN .............................................................................................................................. 5

10.1 Design Summary ............................................................................................................................... 5

11. PATIENT PARTICIPATION .......................................................................................................... 7

12. STUDY DURATION ......................................................................................................................... 7

13. CLINICAL RESEARCH SITE(S) ................................................................................................... 7

14. OVERVIEW of STUDY DEVICES ................................................................................................. 7

14.1 Dexcom G4 Continuous Glucose Monitoring System (System) ........................................................ 7

14.2 Insulin Pump Overview ..................................................................................................................... 8

14.3 Blood Glucose Meter Overview ........................................................................................................ 8

15. OVERVIEW OF PRO INSTRUMENTS ......................................................................................... 9

15.1 Patient Reported Outcome (PROs) Measures .................................................................................... 9

16. DATA COLLECTION AND DATA MANAGEMENT ............................................................... 11

17. STATISTICAL ANALYSIS ............................................................................................................ 11

17.1 Randomization ................................................................................................................................. 11

17.2 Data Analysis ................................................................................................................................... 11

17.3 Cost-effectiveness Analysis: ............................................................................................................ 13

17.4 Sample Size Justification ................................................................................................................. 13

18. STUDY PROCEDURES (Run-in Period) ...................................................................................... 14

18.1 Visit S1 –Screening, Consenting, and Blinded CGM Initiated (Time = 0-14) ................................ 14

18.2 Visit S2 – Week 1 – Blinded CGM Use (Time = 0- 7 days; Window ± 2 days) ............................. 15

18.3 Visit S3 – Week 2 - Run-In Completion, Subject Compliance Assessment, Randomization (Time =

0; Window ± 2 days) Note: .................................................................................................................................... 15

19. STUDY PROCEDURES (PHASE 1) 17

19.1 Visit 1 – Week 1 – CGM Troubleshooting - CGM Group Only (Window ± 2 days) ...................... 17

19.2 Phone Visits (Week 2 Phone & Week 3 Phone): Window ± 2 days) .............................................. 18

19.3 Visit 2 – Week 4 – Follow-Up (Window ± 4 days) ......................................................................... 18


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19.4 Visit 3 – Week 11 – Blinded CGM - SMBG Group only (Window ± 5 days) ................................. 18

19.5 Visit 4 – Week 12 – (Month 3) – Mid Phase 1 Assessment (Window ± 1 days – SMBG; ± 7 days –

CGM) .......................................................................................................................................................... 19

19.6 Visit 5 – Week 23 – Blinded CGM - SMBG Group Only (Window ± 5 days) ................................ 19

19.7 Visit 6 -- Week 24 (Month 6) – Phase 1 Final Assessments (Window ± 1 days – SMBG; ± 7 days –

CGM) & Commencement of Phase 2 ..................................................................................................................... 20

20. STUDY PROCEDURES (PHASE 2 – Follow-up Study) ............................................................. 21

20.1 Visit 1 - Week 26 – Follow-up – CGM/CSII Group Only (Window ± 4 days) ................................ 21

20.2 Visit 2 – Week 30 - Follow-Up (Window ± 4 days) ........................................................................ 22

20.3 Visit 3 – Week 38 (Month 9) –Follow-Up (Window ± 7 days) ....................................................... 22

20.4 Visit 4 – Week 52 (Month 12) – Final Assessment (Window ± 7 days) .......................................... 23

20.5 Device Replacements ....................................................................................................................... 24

21. RISKS ............................................................................................................................ 24

21.1 Sensor Insertion/Use/Removal ......................................................................................................... 24

21.2 Hypoglycemia .................................................................................................................................. 24

21.3 Diabetic Ketoacidosis (DKA) .......................................................................................................... 25

22. Non-Significant Risk Rationale ....................................................................................................... 25

23. ADVERSE EVENTS ....................................................................................................................... 26

23.1 Adverse Event (AE) 26

23.2 Serious Adverse Event (SAE) .......................................................................................................... 26

23.3 Severity of Adverse Events .............................................................................................................. 27

23.4 Relationship of Adverse Event to the Study, Disease, or Device .................................................... 27

23.5 Anticipated Adverse Device Effects ................................................................................................ 28

23.6 Unanticipated Adverse Device Effects ............................................................................................ 29

23.7 MDR Reportable Events/MDR Reporting ....................................................................................... 29

24. ETHICAL CONSIDERATIONS .................................................................................................... 29

24.1 Informed Consent ............................................................................................................................ 29

24.2 Institutional Review Board .............................................................................................................. 30

25. DATA COLLECTION .................................................................................................................... 30

26. DEVICE ACCOUNTABILITY ...................................................................................................... 30

27. MONITORING ............................................................................................................................ 30

28. STUDY TERMINATION ................................................................................................................ 30

29. INVESTIGATOR RESPONSIBILITIES ...................................................................................... 31

30. SPONSOR RESPONSIBILITIES .................................................................................................. 31

31. CONFIDENTIALITY OF RECORDS .......................................................................................... 31

32. REFERENCES ............................................................................................................................ 33

33. APPENDICES ............................................................................................................................ 35

Appendix A: Informed Consent ................................................................................................................ 36

Appendix B: Overall Study Flowchart ..................................................................................................... 37

Appendix C: Clinician Guidelines: General Diabetes Education .......................................................... 38


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Appendix D: Clinician Guidelines for Follow-Up Visits ........................................................................ 39

Appendix E: Visit Flowchart .................................................................................................................... 40

Appendix F: Diabetes Management Guidelines Using CGM ................................................................. 41

Appendix G: Patient Reported Outcome (PRO) Measures ...................................................................... 42

Appendix H: Test and Exam Table ......................................................................................................... 43

Appendix I: Sample CGM Information Guide ........................................................................................ 44

Appendix J: OmniPod Guidance Documents .......................................................................................... 45


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1. ABBREVIATIONS AND DEFINITIONS

A1C Hemoglobin A1C (aka HbA1C)

AE Adverse Event

BGM Blood Glucose Meter

BLINDED CGM Receiver does not display CGM values, trends, or glucose

alerts/alarms in real time. Receiver provides use prompts and features

such as calibration requests, device failures, troubleshooting icons,

event markers, etc.

Carb counting Carbohydrate counting, or "carb counting," is a meal planning

technique for managing blood glucose. Carbohydrate counting helps

to keep track of how much carbohydrate is consumed. A limit for a

maximum amount of carbohydrate is set to maintain glucose levels

within a targeted range.

CBC Complete Blood Count

CF Glucose Correction Factor; as known as insulin sensitivity factor

CGM Continuous Glucose Monitoring

CMP Complete Metabolic Panel

CRA Clinical Research Associate

CRF Case Report Form

CSII Continuous Subcutaneous Insulin Infusion

CT Computed Tomography

DCCT Diabetes Control & Complications Trial

DKA Diabetic Ketoacidosis (as defined by the DCCT) involves all of the

following symptoms such as polyuria, polydipsia, nausea, or

vomiting; serum ketones >1.5 mmol/L or large/moderate urine

ketones; either arterial blood pH <7.30 or venous pH <7.24 or serum

bicarbonate <15; and treatment provided in a health care facility.

DM Diabetes Mellitus

EDC Electronic Data Capture

eGFR Estimated Glomerular Filtration Rate: a renal function test determined

by a blood test for creatinine

EQ5D EuroQol 5D PRO measure

HCP Health Care Professional

Hypoglycemia, Severe Reduced cognitive function, diaphoresis, tachycardia, coma and

seizure. Hypoglycemia is deemed severe if the event required

assistance of another person due to altered consciousness to actively

administer carbohydrate, glucagon, or other resuscitative actions. This

means that the participant was impaired cognitively to the point that

the subject was unable to treat his or herself, was unable to verbalize


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his or her needs, was incoherent, disoriented, and/or combative, or

experienced seizure or coma.

IAH Impaired awareness of hypoglycemia

I:C Insulin to carb ratio, used to determine dosing parameters

ICER Incremental Cost Effectiveness Ratios

IFG Impaired Fasting Glucose IFU Instructions for Use

IGT Impaired Glucose Tolerance

IRB Institutional Review Board

ITT Intent to treat (analysis)

MDI Multiple Daily Injections: Includes a minimum of 3 injections total: 2

injections a day of rapid acting human insulin or analog (an injection

with each major meal) along with 1 daily basal insulin (NPH, detemir,

or glargine).

MDR Medical Device Reporting

mg/dL milligrams per deciliter

MRI Magnetic Resonance Imaging

PC Personal computer, specifically using Intel hardware & MicroSoft

software; not Apple computers

PDM Personal Diabetes Manager: Insulet’s insulin delivery programmer

used with the OmniPod insulin pump.

Personal RT-CGM Personal RT-CGM refers to frequent and continued use of CGM,

owned by the user.

Professional RT-CGM Professional CGM (real time or blinded) is defined as episodic use of

CGM as provided by HCP and owned by physician’s practice.

POC Point of Care (Approved Guideline)

PP Per Protocol (analysis)

PRO Patient Reported Outcome

QALY Quality-Adjusted Life-Years

QoL Quality of Life

RCT Randomized Controlled Trial

RT-CGM Real-Time Continuous Glucose Monitoring System

SAE Serious Adverse Event

SMBG Self-Monitored Blood Glucose

SC Study Coordinator

T1DM Type 1 Diabetes Mellitus

T2DM Type 2 Diabetes Mellitus


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UADE Unanticipated Adverse Device Effect

VAS Visual Analog Scale


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2. INVESTIGATOR SIGNATURE SHEET

I have read the attached protocol and hereby agree that it contains all the necessary details for

performing the study.

I will provide details of the protocol to all members of the study team responsible for conducting

the study.

I will discuss the protocol with them to ensure that all participating staff members are fully informed

regarding the study device and the conduct of the protocol.

Once the Institutional Review Board approves the protocol, I will not modify study procedures

without obtaining prior approval of the Sponsor and, if required, of the Institutional Review Board

(and FDA, as applicable).

I will submit any protocol and/or any informed consent modifications to the Sponsor and the

Institutional Review Board (and FDA, as applicable) and approval will be obtained before any

modifications are implemented.

Investigator's Signature Date

Investigator’s Printed Name


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3. PROTOCOL SYNOPSIS

TITLE Multiple Daily Injections and Continuous Glucose Monitoring

in Diabetes: DIaMonD Study

SPONSOR Dexcom, Inc.

STUDY DEVICE Dexcom G4® Continuous Glucose Monitoring System

(“System”)

STUDY DESIGN Prospective, randomized, parallel arm, controlled trial with 2

phases

HYPOTHESIS Addition of real time continuous glucose monitoring (RT-CGM)

improves glycemic outcome in patients using multiple daily

injections (MDI) and self-monitored blood glucose (SMBG),

who are not at target A1C.

STUDY OBJECTIVES 1) To assess glycemic, health-economic, and quality of life

(QoL) benefits of adding and using RT-CGM in MDI

patients with Type 1 Diabetes Mellitus (T1DM) or Type 2

Diabetes Mellitus (T2DM), not at their A1C goal and relying

on SMBG for diabetes-management decisions.

2) To assess the incremental benefits of changing the insulin

delivery method from MDI to continuous subcutaneous

insulin infusion (CSII) in patients with T1DM already using

RT-CGM. Specific health economics objectives are to evaluate cost

effectiveness and quality of life measures between the two

groups.

For cost effectiveness: Evaluate within-trial cost-

effectiveness attributable to the use of continuous

glucose monitoring (CGM), as well as, the lifetime cost-

effectiveness of the intervention attributable to the use

of CGM.

For quality of life measures: Evaluate diabetes-related

health states and measure health care utilization and

economic consequences attributable to the CGM group

compared to the SMBG group.

STUDY ENDPOINTS Primary Endpoint at Month 6: Change in A1C from baseline

to six months between groups.

Primary Endpoint at Month 12: Change in %Time-in-Range

as determined by CGM from month 6 between groups.

Secondary Endpoints

Month 6 (within and between groups analyses):

Percent A1C ≤ 7%

%Time-in-Range

%Time-in-Hypoglycemia

%Time-in-Hyperglycemia

QoL changes

Cost effectiveness


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Incidence of severe hypoglycemia

Change in hypoglycemia awareness

Changes in glucose variability

Change in SMBG frequency over time

Month 12 (within and between groups analyses)

Percent A1C ≤7% from month 6

Change in A1C from month 6 to month 12




QoL changes

Cost effectiveness



SAMPLE SIZE 338 randomized (assuming a 15% drop rate in Phase 1) for 294

subjects to complete Phase 1:

147 for each diabetes cohort (T1DM and T2DM).

Up to 169 subjects will be randomized per cohort, assuming a

15% drop-out rate in Phase 1.

Up to 500 subjects may be enrolled to achieve randomization of

338 subjects.

STUDY CENTER Up to 35 sites

ENVIRONMENT OF

USE

Home Use

PATIENT POPULATION Adults diagnosed with diabetes mellitus without optimized

glycemic control, using MDI.

INCLUSION CRITERIA

Individuals may be included if they meet the following criteria:

1. Age 25 years or older

2. Diagnosis of T1DM or insulin-requiring T2DM

3. Followed regularly by a physician or diabetes educator

for their diabetes management – with at least 2 office

visits in last year as documented by clinical history

4. Using MDI for at least 12 months prior to study entry

5. Sub-optimal glycemic control, defined as persistent

hyperglycemia, confirmed initially by historical or local

(POC or site’s lab) A1C of ≥7.7% to ≤10%, then

followed with a confirmatory result by central lab of

≥7.5% to ≤10%.

NOTE: Use of a historical local A1C test must be within

1 month of study entry.

6. Desire to lower A1C such as a goal of 7%

7. Stable control of diabetes, as determined per investigator

assessment


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8. Stable diabetes medication regimen for 3 months prior

to study entry

9. Stable weight maintained 3 months prior to study entry,

per investigator’s assessment, and not planning any

structured weight reduction interventions such as

prescription weight loss medications, bariatric surgery,

or protein sparing modified fast during the course of the

study

10. Willing to wear a device (CGM/pump)

11. Willing to avoid use of acetaminophen medications

throughout the study

12. Currently performing SMBG management (by history):

Type 1 – an average of 3 or more times per day; and

Type 2 – an average of 2 or more times per day

13. Able to speak, read, and write English

14. For Phase 2, total daily insulin dose is <100 units

EXCLUSION CRITERIA Individuals will be excluded for any of the following criteria:

1. Use of personal RT-CGM 3 months prior to study entry

(professional CGM use is allowed, whether it was

blinded or un-blinded)

2. Use of CSII 3 months prior to study entry (including

patch pumps)

3. Plan to use personal CGM and/or pump during the

course of the study

4. Addition of any new oral or injectable hypoglycemic

agents (including GLP-1 analogues, Pramlintide, and

SGLT-2 inhibitors – these agents are only for T2DM

subjects) within 3 months prior to study entry. (Use of

these agents does not affect eligibility if used 3 or more

months prior to study entry.) For these medications,

must be on a stable dose, and the GLP-1 medication will

be maintained throughout the study.

Note: These agents should not be added or modified

during course of the study; if use of this class medication

is planned, the patient is not eligible.

5. Use of pre-mixed insulin (e.g. 70/30 or 50/50) 6 months

prior to study entry

6. Current or anticipated acute uses of glucocorticoids

(oral, injectable, or IV), that will affect glycemic control

and impact A1C – such as frequent steroid bursts

required for inflammatory arthritis or inflammatory

bowel disease, recurrent lumbar epidural steroid

injections, etc. (Long-term stable glucocorticoid doses

are allowed, such as when used for the treatment of

rheumatoid arthritis or Addison’s disease).

7. Pregnancy (as demonstrated by a positive test at study

entry screening) or are planning to become pregnant

during the study


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8. Medical conditions that, per investigator determination,

make it inappropriate or unsafe to target an A1C of

<7%, such as, but not limited to, recent cardio- or

cerebrovascular disease, malignancy, severe recurrent

hypoglycemia, or cognitive decline

9. History of visual impairment which would hinder

subject’s participation in the study and perform all study

procedures safely, as determined by investigator

10. History of psychiatric, psychological disorder, or

psycho-social issues that could limit adherence to the

required study tasks

11. Renal disease defined as estimated Glomerular Filtration

Rate (eGFR) <45)

12. Extensive skin changes/disease that preclude wearing

the sensor on normal skin (e.g. extensive psoriasis,

recent burns or severe sunburn, extensive eczema,

extensive scarring, extensive tattoos, dermatitis

herpetiformis)

13. Known allergy to medical-grade adhesives

14. Current participation in another investigational study

(must have completed any previous studies at least 30

days prior to being enrolled in this study)

15. Recent hospitalization or emergency room visit in the 6

months prior to screening resulting in a primary

diagnosis of uncontrolled diabetes

16. Currently abusing illicit drugs, alcohol, or prescription

drugs

17. Any condition per investigator assessment, that could

impact reliability of the A1C measurement, such as (but

not limited to) hemoglobinopathy, hemolytic anemia,

chronic liver disease; chronic GI blood loss, recent red

blood cell transfusion or erythropoietin administration

within 3 months prior to screening

STUDY OVERVIEW This is a prospective, randomized, parallel, controlled study to

be conducted in two phases:

Phase 1- Comparing outcomes of diabetes management using

RT-CGM vs. SMBG alone

Phase 2- Comparing outcomes of insulin delivery via a pump

vs. injections in RT-CGM users.

The DIaMonD study comprises a Run-in period and two

randomization phases. Subjects must successfully complete the

run-in period by demonstrating appropriate self-management

and compliance with CGM and SMBG prior to being

randomized.

Prior to Phase 1, subjects will be asked to undergo a two week

Run-in period, using blinded CGM, for the purpose of assessing


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if willing and able to use CGM in the study and to collect

baseline glucose data.

Eligible subjects will continue on to Phase 1 and will be

randomized to either use RT-CGM (Group 1- CGM) or to

manage their diabetes based on use of SMBG (Group 2- SMBG).

A1C levels will be obtained by central lab determination at

baseline, 3, 6, 9, and 12 months with subjects and site blinded to

central lab results. At six months, subjects in Group 1–CGM

with T2DM and Group 2-SMBG, will complete their

participation in the study.

At six months, subjects with T1DM, in Group 1-CGM who have

been using CGM regularly, are willing to continue RT-CGM, are

using <100 units of insulin a day, and are willing to use an insulin

pump, will proceed on to Phase 2 and undergo a second

randomization. Subjects will all use CGM and will either

continue MDI (Group 1a-CGM/MDI) or change insulin delivery

to CSII (Group 1b-CGM/CSII).

All health utilization will be tracked via 2 mechanisms – self

reporting (e.g., hospital visits, emergency services, home

glucagon use, etc.) and clinic reporting (extra office visits,

additional education, etc.).

Patient reported outcome (PRO) measurements will be obtained

at the beginning and end of each study phase.

STUDY VISIT

OVERVIEW Run-in Period: Eligible subjects will participate in a run-in

period using blinded CGM for up to 3 weeks. The Run-in period

comprises up to 4 clinic visits and concludes with an assessment

of the subject’s compliance to use study devices (including

ability to self-deploy sensors) to continue on to Phase 1 or

terminate from the study.

During the Run-in, subjects will be trained on the study-assigned

meter and CGM use in blinded mode. Baseline data and labs will

be collected. All subjects will return to the clinic after the first

sensor session for assessment and deployment of a second sensor

for the second week of blinded CGM use.

For subjects eligible to continue on to Phase 1, additional

diabetes and device training will be provided, baseline clinical

data will be collected, and baseline PRO instruments will be

administered. Any subject who does not provide ample data from

two sensor sessions due to device issues (i.e., adhesive or sensor

failures) may extend the run-in period in order to collect the total

required baseline data.

Phase 1: Comprises up to 5 clinic visits over 6 months,

depending on randomization group.

Frequency of clinic visits for all subjects is at month 1, 3, and 6.

Additional group-specific visits:


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Group 1-CGM subjects will have a follow-up clinic visit

after the first week of un-blinded CGM use to trouble-

shoot device issues

Group 2-SMBG subjects will use blinded CGM for 1

week at months 3 and 6 to collect glycemic data

During Phase 1 visits, subjects will: 1) be assessed for any AEs

or device issues; 2) have their devices downloaded; 3) have their

diabetes management decisions evaluated by clinicians with

possible adjustments to the diabetes therapy; 4) complete PRO

instruments and 5) have A1C levels drawn.

Ad hoc visits may be conducted throughout the study as needed.

Eligibility to continue on to Phase 2 will be determined upon

completion of Phase 1. Subjects in Group 1-CGM who have

T1DM, have regularly used CGM in month 6, and who are using

<100 units of insulin a day are eligible to continue on to Phase 2

and undergo a second randomization. Subjects will be

randomized to either remain on MDI therapy with CGM (Group

1a-CGM/MDI) or CSII therapy with CGM (Group 1b-

CGM/CSII).

Phase 2: Eligible subjects with T1DM will continue on study for

an additional six months to evaluate the outcome of diabetes

management delivering insulin via CSII vs. MDI in RT-CGM

users. This phase comprises up to 4 clinic visits over 6 months,

depending on secondary randomization group. Group 1b-

CGM/CSII will have additional training and an additional

follow-up visit to troubleshoot for any device issues. In addition,

the insulin regimen will be modified as necessary.

During Phase 2 visits, subjects will 1) be assessed for any AEs

or device issues, 2) have their devices downloaded, 3) have their

diabetes management decisions evaluated with possible

adjustments to the diabetes therapy , 4) be asked to complete

PRO instruments and 5) have A1C levels drawn.

This phase and the study conclude upon review of final CGM

data and completion of PRO measures.

PATIENT DURATION Up to 15 months to allow for screening, follow-up, and

scheduled visit windows.

STUDY DURATION Total study duration is estimated at 2 years.

Full recruitment is estimated at 9-12 months.

Follow-up period is estimated at 13 months.


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4. INTRODUCTION

Diabetes mellitus is a group of diseases characterized by abnormally high blood glucose levels. There

are two major classifications of diabetes mellitus: Type 1 Diabetes Mellitus (T1DM), autoimmune

destruction of the insulin producing pancreatic beta cells resulting in diminished or absent insulin

secretion; and Type 2 Diabetes Mellitus (T2DM), resulting from constellation of defects including but

not limited to impaired insulin action, decreased insulin production, and enhanced hepatic glucose

production.1 The Centers for Disease Control and Prevention reported that diabetes affects

approximately 25.8 million people in the United States, or roughly 8.3% of the population, with

approximately 1.9 million new cases being diagnosed each year. There are also 79 million people in

the United States with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).2 The global

prevalence of diabetes in 2003 was 189 million and it is projected that 324 million people will have

diabetes by the year 2025.3

Large-scale, randomized, prospective trials of various interventional therapies in patients with both

T1DM and T2DM have clearly shown that improved glycemic control significantly reduces the

development and progression of microvascular complications of diabetes in both adults and

adolescents. The Diabetes Control and Complications Trial (DCCT) and the Kumamoto Trials showed

that intensive treatment methods reduced the incidence of these complications by approximately 50 to

70%.4, 5, 6 These studies have demonstrated that intensive monitoring and better control of blood glucose

in people with T1DM and T2DM both delays the onset and reduces the progression of diabetic

retinopathy, nephropathy, and neuropathy. However, the lower A1C in the intensively managed

treatment arm came at the cost of nearly three-fold increase in the risk of severe hypoglycemia.

Subsequent studies have shown that performing as many as seven finger sticks per day was not

sufficient to detect a number of severe hypoglycemic and hyperglycemic events.7 A study by Bode et

al. using a blinded continuous glucose monitoring system (CGM) found that even when patients

performed capillary finger stick measurements as frequently as nine times per day, there were still, on

average, approximately two hours per day of clinical hypoglycemia (<70 mg/dL) and seven hours per

day of clinical hyperglycemia (>180 mg/dL).8

For the above reasons, as well as, to provide the direction and rate of glucose change to help guide

diabetes management decisions, there has been interest in developing devices that measure glucose

frequently, accurately, and automatically. All real-time CGM systems are adjunctive devices with user-

configurable low and high glucose alerts. The Dexcom G4® PLATINUM CGM System (FDA

approved) was deemed safe and effective for use in persons with diabetes 18 years of age and older. In

addition, formative and summative usability studies were conducted on adults using the Dexcom G4™

PLATINUM CGM System. These studies validated the effectiveness of the training, labeling, and

product design.

Two intensive insulin therapies exist for people with T1DM and insulin-requiring T2DM: multiple

daily injections (MDI) and subcutaneous insulin infusion (CSII). In MDI therapy, insulin is

administered via vial and syringe or insulin pen. In CSII, insulin is infused via a catheter inserted under

the skin attached to an external pump. It is estimated that 80% percent of insulin used in the United

States is administered by MDI therapy and that many people still have suboptimal glycemic control.

People with diabetes who treat using MDI therapy have challenges achieving target A1C levels for

numerous reasons. It is known that increased frequency of self-monitoring of blood glucose (SMBG)

levels is correlated with better A1C levels, however, for practical reasons, most patients only perform

no more than four to five glucose measurements per day.


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Consequently, postprandial hyperglycemia and nocturnal hyperglycemia often remain unnoticed, even

in individuals with well-controlled diabetes (by A1C). Therefore, detecting and treating these events

may improve the patient’s glycemic control and have an impact on quality of life. 9

The use of CGM has been studied as an adjunct to intensive insulin therapy with most studies performed

in CSII using patients only. In other studies, there has been little to no distinction made between MDI

and CSII use.10-17

Detailed below, are four studies which compared the response to CGM between study subjects using

CSII and those using MDI; three studies were randomized clinical trials (RCTs), and one was a

prospective-observational study.

In the JDRF study11 in adults greater than 25 years old, 83% of subjects used CSII, 17% used MDI

(9/52 in CGM arm, 7/56 in the control arm). The MDI CGM users reduced A1C −0.54 ± 0.85% vs.

control MDI users raising A1C +0.04 ± 0.34%. In the CSII users, A1C reduced by −0.50 ± 0.51% vs.

control CSII users raising their A1C +0.02 ± 0.47%.

In the Battelino hypoglycemia reduction study12, 24% of subjects in the CGM group used MDI;

whereas, in the control group, 41% used MDI. In this study, time spent hypoglycemic was greater in

the MDI group compared to the pump group -59% vs. -41%, however, the A1C reduction was less

A1C,-0.06% vs. -0.39%.

In the French Evadiac study13, approximately half the participants used MDI. The average A1C

reduction was less in the MDI users, -0.28% vs. -0.67% in those using CSII.

Finally, in the Garg prospective observational study14, the reduction in hypoglycemia was greater in

subjects using MDI, -30% vs. subjects using CSII -21%. However, whether the analysis was intent to

treat (ITT) or per protocol (PP), MDI users had less reduction in the time spent hyperglycemic (ITT-

8.2 to 8.0 hours hyper/day in MDI users, 8.9-6.9 hours hyper/day in CSII users; PP- 8.8 to 8.6 hours

hyper/day in MDI users, 8.4-6.8 hours hyper/day in CSII users).

There have been no prospective randomized controlled studies exploring the clinical benefits of CGM

use solely in poorly-controlled MDI users compared with those who use SMBG as their glycemia

monitoring tool. Therefore, this study will examine the potential benefit of adding CGM to patients

with sub-optimal glycemic control using MDI therapy, and also the potential benefit of adding CSII

therapy in patients randomized to CGM alone.


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5. STUDY OBJECTIVES

The purpose of this study is to:

1) Assess glycemic, health-economic, and quality-of-life (QoL) benefits of adding and using RT-

CGM in MDI patients with T1DM and T2DM not at their A1C goal and relying on SMBG for

diabetes management decisions

2) Assess incremental benefits of changing the insulin delivery method from MDI to CSII in patients

with T1DM already using RT-CGM who are not at their glycemic goals

Specific health economics objectives are to evaluate cost-effectiveness and quality-of-life measures

between the two groups.

For cost effectiveness: Evaluate within-trial cost-effectiveness attributable to use of CGM, as well

as, the lifetime cost-effectiveness attributable to the use of CGM.

For quality-of-life measures: Evaluate diabetes-related health states for patients and measure

health care utilization and economic consequences attributable to the CGM group compared to the

SMBG group.

6. PRIMARY ENDPOINTS

Primary endpoint at Month 6: Change in A1C from baseline to six months between groups.

A 0.4% or greater difference between Group 1-CGM and Group 2-SMBG is considered

clinically significant.

Primary endpoint at Month 12: Change in %Time-in-Range (defined as a glucose value of

70-180 mg/dL) as determined by CGM from Month 6 between groups.

7. SECONDARY ENDPOINTS

Month 6 (within and between group analyses) endpoints:

o Percent A1C ≤ 7%

o %Time-in-Range (70-180 mg/dL)

o %Time-in-Hypoglycemia

o %Time-in-Hyperglycemia

o QoL changes

o Cost effectiveness

o Incidence of severe hypoglycemia

o Change in hypoglycemia awareness

o Changes in glucose variability

o Change in SMBG frequency over time and impact on A1C


o Percent A1C ≤ 7% from month 6

o Change in A1C from month 6 to month 12

o % Time-in-Hypoglycemia

o %Time-in-Hyperglycemia

o Incidence of severe hypoglycemia

o QoL changes

o Cost Effectiveness

o Change in hypoglycemia awareness

o Changes in glucose variability


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8. STUDY POPULATION

The study population comprises adults with T1DM and T2DM mellitus on MDI therapy in Phase 1,

and adults with T1DM in Phase 2.

Determination of classification for diabetes will be based on American Diabetes Association Clinical

Practice Guidelines, accounting for several patient characteristics such as age of onset, patient’s weight

or BMI, history of diabetic ketoacidosis, history of therapy management, and medical records, if

available.

9. STUDY ELIGIBILITY

9.1 Inclusion Criteria

Individuals may be included if they meet the following criteria:

1. Age 25 years of age and older

2. Diagnosis of T1DM or insulin-requiring T2DM

3. Followed regularly by a physician or diabetes educator for their diabetes management – with

at least 2 office visits in last year as documented by clinical history

4. Using MDI for at least 12 months prior to study entry

5. Sub-optimal glycemic control, defined as persistent hyperglycemia, confirmed initially by

historical or local lab (POC or site’s lab) A1C of ≥7.7% to ≤10%, then followed with a

confirmatory result by central lab of ≥7.5% to ≤10%

NOTE: Use of a historical local A1C test must be within 1 month of study entry.

6. Desire to lower A1C such as a goal of 7%

7. Stable control of diabetes, as determined per investigator assessment

8. Stable diabetes medication regimen for 3 months prior to study entry

9. Stable weight maintained 3 months prior to study entry, per investigator’s assessment, and not

planning any structured weight reduction interventions such as prescription weight loss

medications, bariatric surgery, or protein sparing modified fast during the course of the study.

10. Willing to wear a device (CGM/pump)

11. Willing to avoid use of acetaminophen medications throughout the study

12. Currently performing SMBG management (by history):

Type 1 – an average of 3 or more times per day; and

Type 2 – an average of 2 or more times per day

13. Able to speak, read, and write English

14. For Phase 2, total daily insulin dose is <100 units

9.2 Exclusion Criteria

Individuals will be excluded for any of the following criteria:

1. Use of personal RT-CGM 3 months prior to study entry (professional CGM use, blinded or un-

blinded, is acceptable)

2. Use of CSII 3 months prior to study entry (including patch pumps)

3. Plan to use personal CGM and/or pump during the course of the study

4. Addition of any new oral or injectable hypoglycemic agents (including GLP-1 analogues,

Pramlintide, and SGLT-2 inhibitors – these agents are only for T2DM subjects) within 3

months prior to study entry. (Use of these agents does not affect eligibility if used 3 or more

months prior to study entry.) For GLP-1 medications, must be on stable dose and the GLP-1

medication will be maintained throughout the study.


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Note: These agents should not be added or modified during course of the study.

If use of this class medication is planned, the patient is not eligible.

5. Use of pre-mixed insulin (e.g. 70/30 or 50/50) 6 months prior to study entry

6. Current or anticipated acute uses of glucocorticoids (oral, injectable, or IV), that will affect

glycemic control and impact A1C – such as frequent steroid bursts required for inflammatory

arthritis or inflammatory bowel disease, recurrent lumbar epidural steroid injections, etc.

(Long-term stable glucocorticoid doses are allowed, such as when used for the treatment of

rheumatoid arthritis or Addison’s disease).

7. Pregnancy (as demonstrated by a positive test at study entry) at time of screening or are

planning to become pregnant during the study

8. Medical conditions that, per investigator determination, make it inappropriate or unsafe to

target an A1C of <7%. Conditions may include but are not limited to:

Unstable. recent cardiovascular disease,

Recent myocardial infarction

Significant heart failure

Ventricular rhythm disturbances

Recent transient ischemic attack, or cerebrovascular accident

Significant malignancy

Other conditions resulting in physical or cognitive decline

Recurrent severe hypoglycemia

9. History of visual impairment which would hinder subject’s participation in the study and

perform all study procedures safely, as determined by investigator

10. History of psychiatric, psychological disorder, or psycho-social issues that could limit

adherence to the required study tasks

11. Renal disease defined as estimated Glomerular Filtration Rate eGFR <45

12. Extensive skin changes/disease that preclude wearing the sensor on normal skin (e.g. extensive

psoriasis, recent burns or severe sunburn, extensive eczema, extensive scarring, extensive

tattoos, dermatitis herpetiformis)

13. Known allergy to medical-grade adhesives

14. Current participation in another investigational study (must have completed any previous

studies at least 30 days prior to being enrolled in this study)

15. Recent hospitalization or emergency room visit in the 6 months prior to screening resulting in

a primary diagnosis of uncontrolled diabetes

16. Currently abusing illicit drugs, alcohol, or prescription drugs

17. Any condition, per investigator assessment, that could impact reliability of the A1C

measurement, such as (but not limited to) hemoglobinopathy, hemolytic anemia, chronic liver

disease; chronic GI blood loss, red blood cell transfusion or erythropoietin administration

within 3 months prior to screening

10. STUDY DESIGN

10.1 Design Summary

Eligible persons will provide voluntary consent for enrollment into the study (see Appendix A,

Informed Consent).

This is a prospective, randomized, parallel, controlled study that will be conducted in two phases:

Phase 1- Comparing outcomes of diabetes management using RT-CGM vs. SMBG alone

Phase 2- Comparing outcomes of insulin delivery via a pump vs. injections in RT-CGM users (see

Appendix B Study Flowchart)


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Following screening and a Run-in period of blinded CGM use, up to 338 subjects with diabetes

mellitus, not at optimal glycemic control, using MDI, will be randomized. Two diabetes cohorts

(T1DM and T2DM) will be randomized to be independently powered for change in A1C.

Randomization in Phase 1 for the T1DM cohort will be performed using an unbalanced 2:1

randomization scheme resulting in two groups. Group 1-CGM uses CGM as part of their diabetes

management, and will be twice as large as the SMBG group. Group 2-SMBG uses SMBG as per

usual care.

Prior to Phase 1, all subjects will have a run-in period lasting up to 3 weeks in which they will use

the Dexcom™ G4 PLATINUM System in blinded mode to establish compliance with CGM

procedures, willingness to use CGM, and to collect baseline glucose data. Subjects who are willing

and adherent will continue on to Phase 1 and be randomized to either use RT-CGM (Group 1-

CGM) or to manage their diabetes based on use of SMBG (Group 2-SMBG).

Assessment of subject’s willingness to proceed in the study include:

1) Demonstrated ability to comprehend study procedures during the run-in phase, as

evaluated by appropriate research staff

2) Willing to perform required sensor calibrations

3) Willing to wear the device(s) continuously throughout the study

Subjects in both arms will be provided basic diabetes education (See Appendix C: Clinician

Guidelines: General Diabetes Education). Subjects randomized to Group 1-CGM will be instructed

to use the CGM as an adjunct to their current diabetes management regimen to help guide diabetes-

related decisions.

Most of the study visits will be divided into two parts:

1) Part 1: Perform study related tasks. These tasks can be performed by clinical coordinators,

and include tasks such as collecting SAE info, drawing labs, and administering PRO

surveys.

2) Part 2: Provide diabetes management. This will be provided by a clinician well-versed in

MDI therapy, use of real-time CGM, and use of insulin pumps. The time for these

discussions should generally reflect the typical time spent for diabetes management during

a routine, follow-up physician visit. Guidelines for these discussions are included in

Appendix D, Clinician Guidelines for Follow-Up Visits.

Additional visits and phone calls between the scheduled visits are allowed if required for device or

diabetes management issues. Additional diabetes education, if needed per clinician assessment, is

also acceptable in both Groups. Guidelines for follow-up are in Appendix D.

For Group 1-CGM, the CGM downloads will be reviewed with subjects and should be considered

by clinicians to formulate their diabetes management recommendations.

For Group 2-SMBG, downloads will be reviewed with subjects if this is the standard practice of

the site. The blinded CGM downloads will not be reviewed with the subjects and should not be

used or considered by clinicians for diabetes management recommendations.

A1C levels will be obtained at baseline, 3, 6, 9, and 12 months with subjects and sites blinded to

the central lab results.

Note: A1C testing conducted at the clinical site for clinical management

will be obtained at 3, 6, 9, and 12 months by sites’ POC A1C or local lab.

These A1C results can be reviewed with the subjects as part of their routine

visit care.


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At the end of Phase 1, subjects with T2DM, subjects in Group 1-CGM using ≥100 units/day of

insulin, and subjects in Group 2-SMBG will complete their participation in the study.

Those in Group 1-CGM who have T1DM, have used CGM on 21 of the last 28 days, and are using

<100 units/day of insulin are eligible to continue on to Phase 2 and undergo a second

randomization.

During Phase 2, all subjects will use CGM and will either continue MDI therapy (Group 1a-

CGM/MDI) or change insulin delivery to CSII (Group 1b-CGM/CSII). Appendix E, Visit

Flowchart, provides a graphical illustration of the visits time points.

Throughout the course of the study, subjects using CGM will be encouraged to follow diabetes

management guidelines (Appendix F, Diabetes Management Guidelines Using CGM).

All health utilization will be will be tracked via 2 mechanisms:

1. Self-reporting using PRO - Health Service Utilization Form, (e.g. hospital visits,

emergency services, home glucagon use, etc.) and

2. Clinic reporting using the Care Management Form (extra office visits, additional education,

etc.).

Patient reported outcome (PRO) measurements will be obtained at the beginning and end of each

study phase (see Appendix G, PRO Measures, for list of the PRO instruments).

All tests and exams required for the study are listed in Appendix H, Test & Exam Table.

11. PATIENT PARTICIPATION

Up to 15 months to allow for screening, follow-up, and scheduled visit windows.

12. STUDY DURATION

Total study duration estimated at 2 years.

Recruitment estimated at 9-12 months.

Follow-up period estimated at 13 months.

13. CLINICAL RESEARCH SITE(S)

This study will be conducted at up to 35 sites.

Investigational centers will be selected across the United States. Selection is based on each

Investigator’s experience and qualifications, availability of sufficient resources to carry out the required

study procedures and the investigator’s ability to recruit subjects into the study. Enrollment will be

competitive.

14. OVERVIEW of STUDY DEVICES

14.1 Dexcom G4 Continuous Glucose Monitoring System (System)

The Dexcom G4 PLATINUM CGM System is intended for single-patient use. The System was

FDA-approved with Software 505 in October 2014 (PMA# P120005/S018).


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The System continuously tracks and reports glucose values and trending information for people

with diabetes mellitus. The System is designed to provide continuous measurements of glucose

concentrations over a 40-400 mg/dL range.

As part of the System’s instructions for use, users are informed of the following:

System does not replace blood glucose measurements

Blood glucose values may differ from sensor glucose readings and the value from the blood

glucose meter should be used for treatment decisions, such as how much insulin to take. The

direction, rate of glucose change, and trend graph on the system provide additional

information to help with these decisions

Symptoms of high and low glucose should not be ignored. If sensor readings do not fit with

symptoms, blood glucose should be measured with a blood glucose meter

If at any time during use a subject requires a magnetic resonance imaging (MRI) scan,

computed tomography (CT) scan or diathermy treatment, the subject is advised to

discontinue current sensor session prior to the test/treatment, and then replace with a new

sensor after completion of the test/procedure

The device is not approved for use in pregnancy and study participation will be terminated if

a subject becomes pregnant

14.1.1 Dexcom CGM Software

A currently-marketed/FDA-approved Dexcom CGM computer software program will be used

to transfer glucose data stored in the receiver to a site’s computer system, as per their standard

practice. This software may be used in two places:

1. At home, if subjects choose to use the reports and have a personal computer (PC)

2. At the site, for downloading devices for Group 1-CGM to be used for diabetes

management purposes

14.2 Insulin Pump Overview

The insulin pump to be used in this study is the OmniPod, manufactured by Insulet Corporation.

The OmniPod is a wireless, waterproof, insulin pump consisting of two parts:

Wearable Pod

Personal Diabetes Manager (PDM) with a built-in Abbott Freestyle Glucose Meter

Contained within the Pod is an insulin reservoir, angled infusion set, automated inserter, pumping

mechanism and power supply. The OmniPod can hold up to 200 units of insulin; it requires a

minimum of 85 units of insulin to begin operation. Depending on insulin usage, the OmniPod can

be used 48-72 hours.

Subjects who are randomized to add an insulin pump in Phase 2 will be trained on proper insertion

and use. Software used in conjunction with the OmniPod system will be utilized for downloading

data at the sites.

14.3 Blood Glucose Meter Overview

Subjects will use the Bayer Contour Next USB meter to record their blood glucose values

throughout Phase 1 of the study. During Phase 2, subjects randomized to the OmniPod will receive

test strips compatible with the Abbott Freestyle, as this meter is part of the OmniPod PDM. All

other CGM subjects in Phase 2 will continue to use strips for the Bayer Contour Next USB.

Appropriate blood glucose test strips will be provided to subjects throughout their participation in

the study, based on quantities routinely used by the subjects. Software used in conjunction with

Bayer Contour Next USB will be utilized for downloading data at the sites.


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15. OVERVIEW OF PRO INSTRUMENTS

15.1 Patient Reported Outcome (PROs) Measures

15.1.1 PRO measures will be administered at Baseline, 6 and 12 months. PROs will assess

QoL dimensions – health state, psychological well-being, diabetes management, and

interaction with CGM. PROs will also assess treatment satisfaction and behavioral

changes throughout the study, as well as capturing health economic benefits. (See

Appendix G: Patient Reported Outcome (PRO) Measures).

The following PROs will be utilized (all PROs will be captured in electronic data capture, except

EQ-5D-5L, which is paper based):

15.1.2 WHO-5 Well-Being Index18 – This is a validated, 5-question scale, utilized to assess

general outlook and overall well-being. This scale also examines aspects other than

just the absence of depressive symptoms. Administration time is approximately 5

minutes.

15.1.3 EuroQol (EQ-5D)19 – An EQ-5D health state (or profile) is a set of observations

about a person defined by the descriptive system. An EQ-5D health state may be

converted to a single summary index by applying a formula that essentially attaches

weights to each of the levels in each dimension. This formula is based on the

valuation of EQ-5D health states from general population samples. The EQ-5D-5L

consists of a descriptive system and a visual analogue scale (VAS). The EQ-5D-5L

descriptive system comprises the following 5 dimensions: mobility, self-care, usual

activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no

problems, some problems, extreme problems. Time to completion is approximately 5-

10 minutes.

15.1.4 Health Service Utilization Form –

This form captures the frequency of Emergency Room visits, calls to 911, after-

hours/urgent care visits, hospital visits, the number of visits to their health care

provider/physician/nurse practitioner office visits, as well as visits to dieticians. This

form captures these visits whether diabetes-related or not. Additionally, this form

captures self-care time and work/work capability status in relation to their diabetes

needs. Time to completion is approximately 10 minutes.

15.1.5 Diabetes Distress Scale (DDS)20 – This scale lists 17 potential problem areas that

people with diabetes may experience, and can denote the degree to which they are or

are not affected. Administration time is approximately 10 minutes.

15.1.6 Hypoglycemic Fear Survey, Worry Subscale (HFS-W)21 – This validated survey

consists of 18 questions which measure several dimensions of anxiety and fear

surrounding hypoglycemia among adults with diabetes. Administration time is

approximately 10 minutes.

15.1.7 Hypoglycemia Confidence22 – This scale addresses how confident people with

diabetes are to stay safe and avoid serious problems related to hypoglycemia. This scale

consists of 9 questions, with an approximate administration time of 5 minutes.


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15.1.8 Bolus Insulin Questionnaire23 – This scale consists of 8 questions, which asks people

with diabetes to look back at the past week to assess their usage of fast-acting insulin

over breakfast, lunch, dinner, and snacks; also looks at the ease or difficulty of

calculating correct doses. Administration time is approximately 5 minutes.

15.1.9 Diabetes Numeracy Test (DNT5)24 – The Diabetes Numeracy Test is a validated tool

that consists of 5 questions. This is an actual test to determine how accurately a person

with diabetes can calculate commonly ingested carbohydrates. Approximate

administration time is 10 minutes.

15.1.10 Clarke Hypoglycemia Scale25 – A validated tool that uses 8 questions to assess

awareness of hypoglycemia in adults. A score of 1 or 2 is classified as aware; a score

of 3 or more is classified as impaired awareness of hypoglycemia (IAH). Approximate

administration time is 10 minutes.

15.1.11 CGM Expectations Questionnaire26: This questionnaire consists of 5 questions and

looks at potential expectations people with diabetes may have prior to using CGM.

Administration time is approximately 5 minutes.

15.1.12 CGM Attitudes27: This questionnaire consists of 7 questions which will examine how

a person feels about using CGM, based on accuracy, convenience, ease-of-use, general

performance, as well as their trust and confidence in the device. Approximate time is

5 minutes.

15.1.13 CGM Satisfaction28: The CGM Satisfaction scale is a validated tool which consists of

44 questions which assesses satisfaction regarding various aspects of CGM use.

Administration time is approximately 10 minutes.

Prior to randomization, the baseline PROs will be administered to all subjects as follows:

15.1.14 Baseline PROs (Visit S3):

1. WHO-5 Well-Being Index

2. EQ-5D-5L

3. Health Service Utilization Form

4. Diabetes Distress Scale (DDS)

5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W)

6. Hypoglycemia Confidence

7. Bolus Insulin Questionnaire

8. Diabetes Numeracy Test (DNT5)

9. Clarke Hypoglycemia Scale

10. CGM Expectations Questionnaire

15.1.15 Month 6 PROs:

1. WHO-5

2. EQ-5D-5L







9. CGM Attitudes*


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10. CGM Satisfaction*

*Only administered to CGM Group

15.1.16 Month 12 PROs:

1. WHO-5

2. EQ-5D-5L







9. CGM Satisfaction Scale

10. CGM Attitudes

16. DATA COLLECTION AND DATA MANAGEMENT

Data collected during this study will be documented on electronic case report forms (e-CRFs). The

Investigator or designee is responsible for completing the Case Report Forms (CRFs). The EDC

system will be validated prior to study commencement. Sites will be trained on use of the EDC

system by sponsor or designee. Good Documentation Practices principles will be required. Subjects

who fail the Run-In Phase will not undergo randomization and thus will be withdrawn from the

study, with documentation provided on a termination CRF.

A database system, Part 11 compliant, will be created using Jaeb Center’s custom built electronic

data capture system for data entry and verification of the data inputted by site personnel.

17. STATISTICAL ANALYSIS As this is an intent-to- treat (ITT) study, analysis will be conducted on all subjects enrolled at

Months 6 and 12. A second analysis will also be conducted at Months 6 and 12 on the sub-group

of compliant subjects, using an a priori definition for subject compliance to CGM. Compliance is

defined as use of CGM on average a minimum of 6 days during a 7-day wear period (at least 85%

of the days).

17.1 Randomization

For Phase 1, the two diabetes cohorts (T1DM and T2DM) will undergo randomization separately

between Group 1-CGM and Group 2-SMBG and will be stratified by A1C result (<8.5% and ≥

8.5%). Randomization will be performed using a 2:1 randomization scheme for the T1DM cohort

and a 1:1 randomization scheme will be used for the T2DM cohort.

A combination of permuted blocks randomization and stratified randomization will be used. A SAS

program will be written to generate the randomization schedule. For Phase 2, randomization will

be stratified between Group 1a-CGM/MDI and Group 1b-CGM/CSII to ensure equal distribution

for subjects with A1C result ≤ 7%, >7% to <7.5% and ≥7.5%.

17.2 Data Analysis

For Phase 1, the primary endpoint for this study is change in A1C from baseline to six months

between groups. This will be evaluated in the total population and in the T1DM and T2DM

cohorts.

The study hypothesis is:

Ho = A1C delta between Group 1-CGM and Group 2-SMBG = 0


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H1 = A1C delta between Group 1-CGM and Group 2-SMBG ≠ 0

It is anticipated that subjects with T1DM or T2DM who are sub-optimally controlled will show an

improvement in glycemic control with the use of RT-CGM in Group 1-CGM, over and above any

improvement in subjects using SMBG in Group 2-SMBG. Improvement in glycemic control will

be based on the evaluation of the A1C from baseline to 6 months. The magnitude of the change

will be compared between the Group 1-CGM to Group 2-SMBG, using repeated measure of mean

variance analysis.

For Phase 2, the primary endpoint is change in %Time-in-range (70 to 180 mg/dl) as determined

by CGM from month 6 between groups.

Secondary analyses will involve descriptive comparisons and specific health economics modeling

of the following at month 6 and 12 (unless otherwise stated), as applicable:


Percent A1C ≤7%

%Time-in-Range (70 to 180 mg/dL)



QoL changes

Cost effectiveness




Change in SMBG frequency over time


Percent A1C ≤ 7% from month 6

Change in A1C from month 6 to month 12




QoL Changes



Data analysis will be conducted at the completion of the data collection period for all subjects.

Baseline demographic factors will be summarized. For continuous variables, such as age, the mean,

standard deviation, median, and range will be presented. For categorical variables, such as gender,

the proportion of subjects in each category will be presented.

Summary statistics will include the mean, standard deviation, median, and range. 95% confidence

level will be used, when applicable.

Changes in continuous parameters (e.g. A1C, SMBG measurements per day, glucose distribution)

from baseline to follow-up will be analyzed using repeated measures ANOVA, adjusted for the

baseline value and the variables by which the randomization was stratified. Chi-squared tests or

Fisher’s Exact test will be used to analyze categorical data. All null hypotheses will be tested

against two-sided alternatives at the 5% significance level.

Event analysis will be conducted by comparing results experienced by SMBG arm to CGM arm.

Any device-related adverse events (AEs) will be tabulated and reported.


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Missing data will be handled as follows:

For HbA1c data, if the laboratory value is unavailable then the XX value will be used. If neither

measurement is available then the value will be imputed based on available previous lab and/or XX

HbA1c measurements using Rubin’s method.

For CGM data, analyses will include all data available during the randomized trial. Therefore, there

will not be imputation for missing data.

Final analysis of results will be generated using SAS software 9.2 or higher.

17.3 Cost-effectiveness Analysis:

In addition to the data analysis focused on clinical outcomes there will also be a companion analysis

of the economic impact and cost effectiveness of the intervention. The cost-effectiveness analysis

will be detailed in a separate document and is summarized below.

The analyses will address the following objectives:

To collect utilities for diabetes-related health states for patients and to measure health care

utilization and economic consequences attributable to the Group 1-CGM compared to

Group 2- SMBG

To evaluate the within-trial cost-effectiveness of the intervention provided to Group 1-

CGM group compared to Group 2-SMBG

To estimate the lifetime cost-effectiveness of CGM use utilizing a Monte Carlo– based

Markov simulation model to project the course of the natural history of the disease and the

associated spending in both the Group 1-CGM and Group 2-SMBG

For all analyses, the effectiveness parameter will be expressed in terms of quality-adjusted life-

years (QALY) and incremental cost effectiveness ratios (ICER). Cost accounting will vary

according to the time-frame and perspective of the analysis. The within-trial health system

perspective will include all the direct costs associated with the program and all direct and indirect

medical costs accrued by the subjects during the course of the trial. On the other hand, the societal

perspective for the within-trial analysis will also account for the time costs subjects enrolled in the

study.

For the lifetime analysis, investigators will use the Huang, O’Grady and Basu model that was used

in the JDRF CGM trial. The model will be modified to incorporate recent changes in our

understanding of the impact of glucose control on the development of complications, as well as

spending associated with the treatment of diabetes and its complications.

Data to be collected from study subjects at baseline and during the study will include utilities

information for current health, complication related to health states, treatment-related experiences,

medical care utilization and spending, household income, employment, and caregiver time.

Utilities can be directly elicited using three standard methods: the time trade-off (TTO), standard

gamble (SG), and rating scale (RS) or visual-analog scale (VAS). TTO is the most commonly used

for both its ease of understanding and ease of administration. However, it also has drawn some

concern because it asks patients if they would be willing to trade off time at the end of their lives

to be disease free.

Further details will be provided in the detailed Statistical Analysis Plan.

17.4 Sample Size Justification

Phase 1 will be 90% powered to show a difference if the true population value is a difference of

0.4% between the two groups in Phase 1, using a SD of 0.7.


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Phase 2 there will be 80% power to show a difference if the true population value is a difference of

7.5% in Time-in-Range between groups, assuming a standard deviation of 8.0% and a minimum of

50 participants entering and completing phase 2.

A maximum of 338 subjects will be randomized. A sample size of 147 for each diabetes cohort

(total n=294) will allow for both study phases and cohorts to be powered to 90%. Assuming a 15%

drop-rate a total of 169 subjects for each diabetes cohort is required in Phase 1 (T1DM cohort: 113

subjects in Group 1-CGM, and 56 subjects in Group 2-SMBG; T2DM cohort: 85 in Group1-CGM

and 85 in Group 2-SMBG). To achieve randomization sample size, up to 500 subjects may be

enrolled into the Run-in phase of the study.

A 2:1 CGM: SMBG unbalanced randomization scheme will be used in Phase 1 for the T1DM

cohort to ensure that an adequate sample size for Group 1a (CGM/MDI) and Group 1b (CGM/CSII)

will be available to enter Phase 2.

18. STUDY PROCEDURES (Run-in Period)

18.1 Visit S1 –Screening, Consenting, and Blinded CGM Initiated (Time = 0-14)

Potential subjects will be asked to voluntarily provide consent by signing an IRB-approved

informed consent document (Appendix A: Informed Consent). The investigator or designee will

explain the nature, purpose, expected duration, and risks associated with study participation.

Potential subjects will have the opportunity to ask questions and receive answers from study staff.

All subjects will be provided a copy of the signed informed consent document.

Subjects who have indicated willingness to participate by signing the informed consent document

and who meet the inclusion and exclusion criteria are eligible to participate in the study. Subjects

in each diabetes cohort (T1DM and T2DM) will be given different informed consent documents to

reflect that Phase 2 of the study is only applicable to subjects having T1DM.

All subjects will be considered enrolled in the screening phase of the study once subjects’ sign the

informed consent. Regarding study entry A1C confirmation, if the most recent historical A1C is

outside the 1 month window from study entry sites will need to draw a POC or local lab A1C for

eligibility confirmation (Sites that do not have a POC or on-site lab, may split this visit.)

Eligible subjects who sign the informed consent document will have the following tests/exams,

devices and training provided during this visit:

o Screening A1C (POC or local lab), confirm ≥7.7% and ≤10% (POC or local lab results may

be historical if results available 1 month prior to consent date.) If yes, then continue

collection of remaining visit labs and data. o Pregnancy test (urine) will be completed for women of childbearing potential (test

conducted within 72 hours of sensor insertion).

o Labs:

o Central Lab –

A1C; Note: via a method approved by the National Glycohemoglobin

Standardization Program (NGSP)29

o Local Labs –

Complete Metabolic Panel (CMP) which includes liver and kidney function fasting

or non-fasting (if obtained within 3 months, may use historical)

C-peptide, fasting or non-fasting (may use historical if obtained within the last 6

months)

CBC (if obtained within 3 months may use historical)


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Total cholesterol, fasting or non-fasting (if obtained within the last 12 months may

use historical)

o Vital Signs

o Basic demographic information

o Height & Weight (for BMI)

o Download current blood glucose meter(s) (if possible) to assess baseline SMBG frequency.

If the meter(s) is not available, it can be brought to the next visit.

o Study-assigned blood glucose meter, strips, and training as needed

o Initial CGM training/core tasks:

Insertion steps

Calibration

Troubleshooting

o Blinded CGM insertion and initial calibration (CGM receiver blinded using SweetSpot.

Ensure receiver is blinded – receiver screen will read “Display Off” if properly blinded.)

o Home use instructions, such as CGM basic troubleshooting

Subjects will be provided a blood glucose meter and test strips to use for all SMBG testing. Test

strips will be allocated at each study visit. Instruction on blood glucose meter use will be provided.

Subjects will be advised that MRIs, diathermy, and CT scans are not compatible with the CGM

sensor. In the event a subject needs to have an MRI or CT scan during course of the study, their

current sensor will to be discontinued prior to any of these tests per the IFU.

18.2 Visit S2 – Week 1 – Blinded CGM Use (Time = 0- 7 days; Window ± 2 days)

All subjects return after one week of initiation of the blinded-CGM wear to identify any challenges

with wearing or using the CGM device. Subjects will be guided how to self-deploy a second device

for a second week of data collection, or if preferred by the subject, study staff may deploy at this

visit.

Study staff will-

Obtain CGM and Blood Glucose Meter (BGM) data, per usual practice

Assess any AEs or device issues

Upload devices to SweetSpot, and assess CGM and BGM compliance using the utilization

reports. Subjects will be terminated if non-compliant. The investigator and team will assess

subject’s eligibility to continue in the study based on adherence to CGM and study

procedures. Compliance definition for continuing on in the study is established as:

o CGM Adherent - 85% of days with wearing CGM sensor , carrying the receiver

AND calibrating 2 times/ calendar day (approximating the 12-hour calibration

scheme)

o SMBG Adherent - Minimum of 3 or more fingersticks daily for BG monitoring

(inclusive of calibration measurements) for Type 1; minimum of 2 or more

fingersticks daily for BG monitoring (inclusive of calibration measurements) for

Type 2 o Medications: Avoidance of acetaminophen-containing medications

Inform subject that they must be able to self-deploy sensor by Screening Visit 3 (required

if randomized to CGM group).

18.3 Visit S3 – Week 2 - Run-In Completion, Subject Compliance Assessment, &

Randomization (Time = 0; Window ± 2 days)


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Study staff will -

Upload meter and CGM data to SweetSpot

Note: In the event the subject was unable to collect a minimum of 12 days of CGM

data during the 2 weeks of baseline blinded CGM data due to device issues, not

compliance issues (i.e., adhesive or sensor failures) they may have their Run-in period

extended for 1 additional week in order to collect this baseline data. This extension

would be at the discretion of the investigator.

Assess any AEs or device issues that may have occurred since the last study visit

Assess compliance using SweetSpot utilization report. Subjects will be terminated if non-

compliant. The investigator and team will assess subject’s eligibility to continue in the

study based on adherence to CGM and study procedures. Compliance definition for

continuing on in the study is established as:

o CGM Adherent - 85% of days (e.g. 12 out of 14 days in a 2 week period).

Includes wearing CGM sensor ,carrying the receiver AND calibrating 2

times/calendar day (approximating the 12-hour calibration scheme)

o SMBG Adherent - Minimum of 3 or more fingersticks daily for BG monitoring

(inclusive of calibration measurements) for Type 1; minimum of 2 or more

fingersticks daily for BG monitoring (inclusive of calibration measurements) for

Type 2 o Medications: Avoidance of acetaminophen-containing medications

Assess subject’s ability to self-deploy sensor (required if randomized to CGM group)

Subjects are eligible to continue in the study if:

o Willing and compliant with CGM and BGM during the Run-in period

o Central lab A1C result is confirmed within eligibility range: ≥7.5% to ≤10%

Note: site is blinded to actual central lab result; however, site will be notified

whether subject’s central lab was within range for study eligibility.

Obtain concomitant medications (not vitamins/minerals) including dose and frequency,

and if subject takes as needed (p.r.n.). Assess for addition or modification of any GLP-1

agonists, pramlintide, and SGLT-2 inhibitors.

If these medications are added prior to randomization, the subjects will be

withdrawn from the study. Administer baseline PROs to all eligible subjects:

1. WHO-5 Well-Being Index

2. EQ-5D-5L



5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W



8. Diabetes Numeracy Test (DNT5)


10. CGM Expectations Questionnaire

Randomize per EDC procedures on the study website:

o RT-CGM (Group 1-CGM)

o SMBG (Group 2-SMBG)


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Retrieve CGM Systems from subjects randomized to Group 2-SMBG and maintain

systems with proper identification for future study use with same subject

Un-blind CGM receiver for subjects in Group 1-CGM

o Train RT-CGM group on the use of the Dexcom G4 System in real-

time mode, which includes:

Sensor insertion

CGM calibration

Focused instruction about alerts

Using the direction and rate of glucose change for diabetes

management

Troubleshooting

Provide and review the “Diabetes Management Guidelines

Using CGM” (Appendix F)

Obtain abbreviated medical and diabetes history

Schedule or provide general diabetes self-management education with

clinician (see Appendix C, Clinician Guidelines: General Diabetes

Education)

Establish and review glucose targets with each subject (clinician)

Inform each subject’s treating physician and/or primary care physician

regarding their patient’s involvement in the study

Set initial alerts settings for subjects in the CGM group (clinician)

Download CGM and Blood Glucose Meter (BGM) data, per usual practice for

diabetes management (clinician)

19. STUDY PROCEDURES (PHASE 1)

19.1 Visit 1 – Week 1 – CGM Troubleshooting - CGM Group Only (Window ± 2 days)

This visit is scheduled one week after randomization to perform the following:

Upload meter and CGM data to SweetSpot

Modify subject’s CGM alerts based on their experience (clinician)

Assess for any AEs or device issues

Subject will deploy a new CGM sensor, or staff will guide subject to deploy a new CGM

sensor (if the subject is unable to deploy on their own)

Provide each subject with additional sensors to deploy at home until they return for Week

4 visit

Teach and encourage subjects with home PCs to download their CGM devices (clinician)

Dispense test strips


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Provide and review the “Diabetes Management Guidelines Using CGM” (Appendix F)

(clinician)

Download and review CGM with subjects to assess calibration, reinforce the need to

calibrate, and for diabetes management (clinician)

Study staff will train subjects who are willing and able to download CGM data on Dexcom CGM

software. From here, subjects can view their glucose trends which will give them their personal

data for review. If desired, subjects may send their data via email (PDF) or print their results to

share with their clinician.

Ad hoc follow-up phone calls and/or visits may be performed to address any questions on CGM

use from the subject.

19.2 Phone Visits (Week 2 Phone & Week 3 Phone): Window ± 2 days)

All subjects will receive a follow-up phone call at Week 2 and Week 3 to assess their overall

feedback, ability to deploy sensors and set-up system (for those in the CGM group), and to answer

any questions the subject may have.

Glucose data may be reviewed (if the subject is able to download at home) and therapy adjusted.

Ad hoc visits may be added as needed, that may include device downloads.

19.3 Visit 2 – Week 4 – Follow-Up (Window ± 4 days)

Study staff will -

Upload meter and CGM data to SweetSpot database

Troubleshoot CGM and/or SMBG issues


Obtain concomitant medications including dose and frequency (not vitamins/minerals),



o In the event the subject begins GLP-1 agonists, pramlintide, or SGLT-2 inhibitors

during the study, those subjects will still be allowed to participate in future study

visits.

Provide additional education to either group if required per clinical assessment (clinician)

Review and assess subject per Appendix D: Clinician Guidelines for Follow-Up Visits

(clinician)

Make adjustments to diabetes therapy, if indicated (clinician)


Download CGM and BGM data, per usual practice for diabetes management (clinician)

For the CGM group-

Provide and review the “Diabetes Management Guidelines Using CGM” (Appendix F)

(clinician)

Dispense additional sensors to deploy at home for weekly insertions until they return for

their Week 12 visit

19.4 Visit 3 – Week 11 – Blinded CGM - SMBG Group only (Window ± 5 days)


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The purpose of this visit is to have subjects wear blinded CGM for one sensor session. Subjects

will return the CGM at Week 12 Visit.

At this visit the following will be done:


A CGM sensor will be inserted in blinded mode (self-deployed or assisted by study staff)

and subjects will be provided CGM training and core tasks to include calibration, and

troubleshooting. (Subjects are asked to contact the site if any sensor/adhesive issues arise

within the first 3 days of wear for sensor replacement.)

19.5 Visit 4 – Week 12 – (Month 3) – Mid Phase 1 Assessment (Window ± 1 days – SMBG;

± 7 days – CGM)

Study staff will -


Troubleshoot CGM and/or SMBG issues


Obtain concomitant medications (not vitamins/minerals). Assess if subject takes as needed

(p.r.n). Assess for addition or modification of any GLP-1 agonists, pramlintide, and SGLT-

2 inhibitors.



visits.

Provide additional education to either group, if required per clinical assessment (clinician)

Review and assess subject per Appendix D: Clinician Guidelines and Follow-Up Visits

(clinician)



Complete POC A1C (via POC or local lab); these results may be shared with the subject

Draw blood for A1C assessment. Note: Results of central lab A1C will not be shared with

the subject

Record Height and weight (for BMI)

Retrieve blinded-CGM from Group 2-SMBG. (NOTE: If subject’s sensor/adhesive failed

within the first 3 days during this one week of blinded wear, they were instructed to contact

the site for a new sensor to be inserted.)

CGM group subjects, provide additional sensors to self-deploy weekly until they return for

Week 24 visit

CGM group subjects, provide and review Appendix F: Diabetes Management Guidelines

Using CGM (clinician)


19.6 Visit 5 – Week 23 – Blinded CGM - SMBG Group Only (Window ± 5 days)


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The purpose of this visit is to have subjects wear blinded CGM for one sensor session. Subjects

will return their blinded-CGM at Week 24 Visit.

At this visit the following will be done:


A CGM sensor will be inserted in blinded mode (self-deployed or assisted by study staff)

and subjects will be provided CGM training on core tasks to include calibration, and

troubleshooting. (Subjects are asked to contact the site if any sensor/adhesive issues occur

within the first 3 days of wear for sensor replacement.)

19.7 Visit 6 -- Week 24 (Month 6) – Phase 1 Final Assessments (Window ± 1 days – SMBG;

± 7 days – CGM) & Commencement of Phase 2

Follow-up assessments for eligibility to continue onto Phase 2 for Group 1-CGM, and end-of-

study tasks will occur during this visit. The following subjects complete the study at the end of

Phase 1:

Subjects who have T2DM

Group 1-CGM subjects who are using ≥100 units/day of insulin

Group 2-SMBG subjects

Study staff will -








visits.



the subject


Record height and weight (for BMI)

CGM group subjects, provide and review Appendix F: Diabetes Management Guidelines

Using CGM (clinician)

Administer PROs:

1. WHO-5

2. EQ-5D-5L



5. Hypoglycemic Fear Survey – Worry subscale (HFS-W)





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9. CGM Attitudes*

10. CGM Satisfaction Scale* *NOTE: CGM Satisfaction and CGM Attitudes are administered only to Group 1- CGM.

Retrieve blinded-CGM from Group 2-SMBG (NOTE: If subject’s sensor/adhesive failed

within the first 3 days during this one week of blinded wear, they were instructed to contact

the site for a new sensor to be inserted.)


Complete Care Management Form to assess clinic visits unrelated to study visits (See

Section 10)

For subjects not continuing on to Phase 2:

Subjects in Group 2-SMBG will be offered a trial of real-time CGM (using a FDA-approved CGM

System) and, if interested, will be trained on basic RT-CGM. Follow-up will be provided after the

2-week trial is complete, according to site’s standard-of-care with CGM follow-up.

If the subject desires to continue with CGM and the investigator believes CGM is clinically

warranted for the particular subject, a prescription will be written for sensors and follow-up

communication with their treating physician will be made. Their prescription will be communicated

with the subject’s treating physician.

Subjects in Group 1-CGM not continuing onto Phase 2 will have a review of Diabetes Management

Guidelines. They will be provided a prescription for CGM, if desired and the investigator believes

CGM is clinically warranted for the particular subject. Their prescription will be communicated

with the subject’s treating physician.

For subjects continuing on to Phase 2:

Eligible subjects with T1DM in Group 1-CGM, using <100 units/day of insulin and who used CGM

21 out of 28 days within the last month, will be asked if they are willing to participate in Phase 2.

If eligible and willing to continue, subjects will be randomized to one of the following groups:

MDI with CGM (Group 1a-CGM/MDI)

CSII with CGM (Group 1b-CGM/CSII)

For all subjects who enter Phase 2:

Offer carbohydrate counting instruction (individual or group training)

Group 1a-CGM/MDI subjects will meet with a clinician to discuss any further questions

they have regarding diabetes management

Group 1b-CGM/CSII subjects will be provided a study-assigned pump, PDM, and will

receive insulin pump-related training on device set-up and use

o Initial pump settings will be determined and discussed

o Additional visits for pump training can be scheduled as needed

Subjects will be provided sensors and strips to cover the weeks between visits.

Insulin pods are provided to subjects randomized to Group 1b-CGM/CSII

Randomization in this phase will be stratified between Groups 1a and 1b to ensure even distribution

for subjects with A1C result ≤ 7%, >7% to <7.5% and ≥7.5%

20. STUDY PROCEDURES (PHASE 2 – Follow-up Study)

20.1 Visit 1 - Week 26 – Follow-up – CGM/CSII Group Only (Window ± 4 days)


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Study staff will-

Upload CGM and BGM to SweetSpot database

Download OmniPod data onto a centrally-located computer

Troubleshoot any pump/device issues

Assess any AEs or device issues, specifically related to the pump






visits.

Provide and review Appendix D Clinical Guidelines for Follow-up Visits; and Appendix

F: Diabetes Management Guidelines Using CGM (clinician)

Make pump adjustments. Note: pump adjustments may require frequent visits, and follow-

up phone calls. These ad hoc visits will be documented as part of pump training. (clinician)

Dispense diabetes supplies – pods (Group 1b only), test strips, sensors to deploy at home

until they return for their Week 30 visit


20.2 Visit 2 – Week 30 - Follow-Up (Window ± 4 days)

Study staff will -

Upload meter, CGM, to SweetSpot database


Troubleshoot any CGM, BGM or pump issues





F: Diabetes Management Guidelines Using CGM Dispense diabetes supplies – pods

(Group 1b only), strips and additional sensors to deploy at home until they return for their

Week 38 visit (clinician)

Download CGM, BGM and pump data, per usual practice for diabetes management

(clinician)

20.3 Visit 3 – Week 38 (Month 9) –Follow-Up (Window ± 7 days)

Study staff will-

Upload BGM, CGM, and OmniPod PDM data to SweetSpot database


Troubleshoot any CGM, BGM or pump issue






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visits.

Obtain CGM, BGM and pump data, per usual practice Provide additional education to

either group if required per clinical assessment (clinician)



F: Diabetes Management Guidelines Using CGM (clinician)


the subject


Dispense diabetes supplies – pods (Group 1b only), strips and additional sensors to deploy

at home until they return for their Week 52 visit


(clinician)

20.4 Visit 4 – Week 52 (Month 12) – Final Assessment (Window ± 7 days)

This visit signifies Phase 2 completion.

Study staff will -

Upload meter, and CGM, to SweetSpot database






Assess compliance (SC), and make final evaluation of subjects’ diabetes management

decisions (clinician).

Draw final blood for A1C assessment. Note: Results of central lab A1C will not be shared

with the subject.


Administer PRO surveys

Collect OmniPod PDM, collect CGM if not clinically warranted/desired. . Note: Subject

may be prescribed the CGM System and pump per Investigator’s assessment, if requested

by the subject.


(clinician)

Complete Care Management Form to assess clinic visits unrelated to study visits (See

Section 10)

PROs to be administered at Month 12 include:

1. WHO-5

2. EQ-5D-5L



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5. Hypoglycemic Fear Survey – Worry subscale (HFS-W)




9. CGM Satisfaction Scale

10. CGM Attitudes

20.5 Device Replacements

Dexcom G4 PLATINUM components that malfunction or are lost during the course of the study

may be replaced at any time at the discretion of the Investigator and Sponsor.

21. RISKS

21.1 Sensor Insertion/Use/Removal

Insertion of the sensors into the skin may result in pain, erythema, and/or edema at the insertion

sites. Infection, excessive bleeding, or hematoma are also possible side effects of device use;

however, the expected frequency of these events is low based on data obtained from similar devices

and adverse event information from more than five previous Dexcom studies where the device was

inserted from 12 hours to 15 days.

After removal of the sensors, subjects may experience irritation due to the medical adhesive used

to apply the sensor pod and any bandages that may be placed over the device. This reaction is self-

limiting and should resolve within hours and not more than a week post-removal. Subjects may

experience some itching in the area during the healing process, which is normal.

Rarely, subjects may develop an allergic reaction to one or more of the components of the sensor

and/or transmitter. This is similar to allergies that can occur due to contact with medical tape.

Sensors may fracture in situ on rare occasions. In these rare instances when this has occurred in the

past, consulting physicians and surgeons have recommended not to remove the wire fragment from

beneath the skin as long as there are no symptoms of infection or inflammation. In the event that

signs and/or symptoms of infection or inflammation arise such as redness, swelling, and pain

subjects should consult with the investigator or prescribing physician for the best course of action.

If there is no portion of the broken sensor wire fragment visible above the skin, attempts to remove

it without medical guidance are not advised.

A thermal burn due to the electrical components of the device is not a risk as the circuit designed

and verified to limit the intra-electrode current to a maximum of 20 µAmps. Given that any level

less than 1 µAmp is considered safe, per ISO 14708-1 and EN45502-1, the device’s maximum

current output is 2 percent of the 1 µAmp limit.

21.2 Hypoglycemia

Treatment of diabetes is associated with increased risk of severe hypoglycemia. Hypoglycemia may

be associated with reduced cognitive function, diaphoresis, tachycardia, coma, and seizure. These

complications are an inherent risk of having diabetes. Subjects will be required to use blood glucose

meter (not CGM) values to guide all diabetes-related therapeutic decisions (e.g. insulin dosing

modifications) to minimize the risk of treatment errors.

Severe hypoglycemia will be captured as a serious adverse event if the event required assistance of

another person due to altered consciousness to actively administer carbohydrate, glucagon, or other

resuscitative actions. This means that the participant was impaired cognitively to the point that the

subject was unable to treat his or herself, was unable to verbalize his or her needs, was incoherent,


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disoriented, and/or combative, or experienced seizure or coma. If these criteria are not met but

emergency evaluation or treatment was obtained from a health care provider the event will be

captured as an Adverse Event and not a Serious Adverse Event unless one of the criteria for SAE

is met.

21.3 Diabetic Ketoacidosis (DKA)

Subjects may also be randomized to use a currently-marketed insulin pump during Phase 2. Due

to the use of insulin, there are risks of hypoglycemia and associated symptoms related to the

infusion of insulin.

Diabetic ketoacidosis is a serious complication of diabetes that occurs when the liver produces high

levels of ketones, which are an acid. Diabetic ketoacidosis develops when there is insulin

deficiency; in response the body switches to burning fatty acids and producing acidic ketone bodies

that cause most of the symptoms and complications. Vomiting, dehydration, tachypnea, confusion

and occasionally coma are symptoms.

DKA will be captured as a serious adverse event if confirmed and treated. Hyperglycemia that

does not meet criteria for definite or probable DKA is reported as an Adverse Event if emergency

evaluation or treatment was obtained from a health care provider; these events are considered

Adverse Events and not Serious Adverse Events unless one of the criteria for SAE is met.

Subjects may also be randomized to use a currently-marketed insulin pump during Phase 2. Due to

the use of insulin, there are risks of hyperglycemia and associated symptoms related to potential

interruptions of insulin delivery.

22. Non-Significant Risk Rationale

The Dexcom Continuous Glucose Monitoring System described in this protocol is considered by

the Sponsor to be of non-significant risk as it does not meet the definition of a significant risk

device per 21 CFR 812.3(m), in that:

It is not an implant nor presents a potential for serious risk to the health, safety or welfare

of a subject;

CGM devices are not purported or represented to be for use in supporting or sustaining

human life and thus do not present a potential for serious risk to the health, safety, or

welfare of a subject; or

Use of CGM devices does not present a potential for serious risk to the health, safety or

welfare of a subject.

The following information supports a non-significant risk determination for the device that will be

used in this protocol:

FDA-approved Dexcom CGM Systems have been considered a non-significant risk

device;

The CGM device and insulin pump used in this study are being used on label in intended

population;

The Medtronic-Minimed Guardian RT® CGMS, a FDA approved device using similar

technology, has been considered a non-significant risk device;

The FreeStyle Navigator® CGMS, a FDA-approved device using similar technology, has

been considered a non-significant risk device;

The insertion needle thickness used in the device is not significantly thicker than the

needles used in syringes for insulin injection and the needle insertion depth is less than 0.5

inches;

None of the expected device-related adverse events as defined in the protocol and

associated documents (e.g. Instructions for Use) would be life-threatening or would result

in any permanent impairment of a body function or permanent damage to a body structure;


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There are no expected electrical safety risks as the device has passed the electrical safety

tests as per EN45502-1 and EN60601;

If the subject feels any discomfort during the course of the study, he/she will be able to

remove the device immediately (the device is not permanent);

The device is being used to complement, not replace, self-monitoring of blood glucose

meter information and readings are not intended to be used alone to make diabetes self-

management decisions. As with the currently approved device and per intended use of

similar technologies, subjects in the study will be instructed not to use the device for

diabetes therapy or management;

Subjects will be instructed to monitor their blood glucose levels as per their usual practice.

A recently completed Dexcom-sponsored study, conducted for regulatory purposes (FDA),

concluded that the safety profile of the System is comparable to the initial Dexcom G4

Platinum CGM System for adults.

23. ADVERSE EVENTS

At all study visits, study staff will determine if any device or study-related adverse events (AEs) have

occurred. Disease related events that are chronic in nature and occur as part of the progression of the

diabetes disease state (i.e. diagnoses of retinopathy, nephropathy, neuropathy) will not be captured as

adverse events in this study.

Confirmed DKA and severe hypoglycemic events will be captured as adverse events, as well as

captured on separate event CRFs - a DKA Event Form, or a Severe Hypoglycemic Event Form,

respectively. These event-specific forms will be utilized to capture additional details surrounding each

event, if known. All confirmed DKA and severe hypoglycemic events, per protocol definition (see

Section 1. Abbreviations and Definitions), will be considered Serious Adverse Events (SAEs).

Therefore, a SAE form will always be completed for any confirmed DKAs and severe hypoglycemic

events which occur during the course of this study.

Hypoglycemic events are also considered reportable adverse events if the criteria for severe

hypoglycemia are not met but emergency evaluation or treatment was obtained from a health care

provider; these events are considered Adverse Events and not Serious Adverse Events unless one of the

criteria for SAE is met.

Hyperglycemia that does not meet criteria for definite or probable DKA is reported as an Adverse Event

if emergency evaluation or treatment was obtained from a health care provider; these events are

considered Adverse Events and not Serious Adverse Events unless one of the criteria for SAE is met.

All study or device-related AEs will be monitored until adequately resolved or stable.

For purpose of this protocol, AEs will be captured on the AE CRF form if causality is related to the

study, or device. AEs are categorized as follows:

23.1 Adverse Event (AE)

Any clinically significant undesirable experience (sign, symptom, illness, or other medical event)

meeting the causality definition above that appears or worsens in a subject during a clinical study.

A clinically significant event is any event (sign, symptom, lab/imaging abnormality, or diagnosis)

that is noteworthy enough to merit documentation in standard medical records (e.g. history and

physical, progress notes, clinic visit notes, etc.). Other non-clinically significant events (e.g. colds,

minor headaches, etc.) may be documented on source documents only.

23.2 Serious Adverse Event (SAE)


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A serious adverse event (SAE) is defined as any AE that is fatal, life-threatening, results in

persistent or significant disability or incapacity, requires medical or surgical intervention to prevent

permanent impairment or damage, or results in initial (in-patient) hospitalization or prolongation

of hospitalization. Life-threatening is defined as the substantial risk of dying at the time of the

adverse event or suspicion that continued use of the device would result in a subject’s death.

Any SAE, including death, due to any cause (related or unrelated to the device), that may occur

during a clinical study must be reported immediately (within 2 working days of learning of the

event). Details of the SAE submitted via eCRF will result in an automatic email generated and

forwarded to the Sponsor. The Sponsor contact for SAE review:

David Price, MD

Vice President, Medical Affairs

Dexcom, Inc.

6340 Sequence Drive

San Diego, CA 92121

Telephone: (858) 875-9525

Fax: (858) 332-0200 Email: [email protected]

Dexcom Clinical Affairs personnel will document SAE details and assessment by Clinical Affairs

management in a timely manner.

23.3 Severity of Adverse Events

The following definitions may be used to rate severity of AEs:

23.3.1 Mild

Awareness of signs or symptoms, but easily tolerated; are of minor irritant type;

causing no loss of time from normal activities; symptoms would not require medication

or a medical evaluation; signs and symptoms are transient.

Example: hypoglycemia with at home treatment by subject or friend/family member.

23.3.2 Moderate

Discomfort severe enough to cause interference with usual activities, requiring

treatment but not extended hospitalization or intensive care for the subject.

Example: hypoglycemia with seizure involvement, requiring treatment with glucagon

and/or an emergency room visit.

23.3.3 Severe

Incapacitating, causing inability to do work or usual activities; signs and symptoms

may be of systemic nature or require medical evaluation and/or treatment, requiring

additional hospitalization or intensive care (prolonged hospitalization).

Example: hypoglycemia with seizure involvement, requiring hospitalization.

23.4 Relationship of Adverse Event to the Study, Disease, or Device

The investigator will categorize the relationship of the event to the study, disease, or study device

as follows:

23.4.1 Not Related

AE is due to an underlying disease state or concomitant medication or therapy not

related to the device, disease or study.

23.4.2 Probably Not Related

mailto:[email protected]


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AE has minimum or no temporal relationship to the device, disease or study

participation and/or a more likely alternative etiology exists.

23.4.3 Possibly Related

AE has a strong temporal relationship to the device, disease or study procedures and

alternative etiology is equally or less likely compared to the potential relationship to

the device, disease or study.

23.4.4 Probably Related

AE has a strong temporal relationship to the device, disease or study and another

etiology is unlikely.

23.5 Anticipated Adverse Device Effects

The following events have been identified as possible device-related adverse events of sensor

insertion and wear:

Excessive pain or discomfort from system deployment (8 or greater on a 10-point

Likert scale)

Excessive bleeding

Hematoma (slight ecchymosis is a known consequence of needle skin puncture and

will not be captured as an AE)

Excessive edema from sensor and/or adhesive tape that is significant and non-resolving

within 48 hours of sensor pod removal

Excessive erythema from sensor and/or adhesive tape that is significant and non-

resolving within 48 hours of sensor pod removal

Local infection

Sensor or introducer needle fracture during insertion/wear/removal

Degrees of edema, erythema, or infection that may occur at the sensor insertion or adhesive tape

site will be assessed by the subject and documented for review by study staff. An AE will be

recorded as severe in intensity if skin appearance indicates significant edema or erythema (per

definition above) and/or if infection, defined as the presence of pus, at the sensor insertion or

adhesive tape site occurs.

The following events have been identified as possible device-related AEs of insulin pump use,

infusion of insulin and potential interruptions of insulin delivery:

Localized infection

Skin irritation/erythema /rash (slight irritation/ erythema will not be captured as an AE)

Hematoma (Slight ecchymosis is a known consequence of needle skin puncture and

will not be captured as an AE)

Discomfort/pain deployment (8 or greater on a 10-point Likert scale)

Bleeding, excessive

Diabetic Ketoacidosis (DKA)

Severe hypoglycemia

Information regarding device-related AEs that occur during the study will be entered into

appropriate CRFs. Such information will include, at a minimum:

Date of event

Severity

Outcome

Resolution of event

Causality to study devices and procedures


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23.6 Unanticipated Adverse Device Effects

An unanticipated adverse device effect (UADE) is not expected to occur. An UADE is defined as

any serious adverse effect on health or safety or any life-threatening problem or death caused by –

or associated with – the device, if that effect, problem, or death was not previously identified in

nature, severity, or degree of incidence in the investigational plan (including documents such as the

protocol, the informed consent document, other study-related documents), or any other

unanticipated serious problem associated with the device that relates to the rights, safety, or welfare

of subjects.

During the review of a reported SAE, if Clinical Affairs management with the Investigator input

determines the severity or extent of the event was not cited in this protocol or associated protocol

materials, and the event was classified as, ‘possibly related’ to the device, the event will be

documented as an UADE. If the event is classified as an UADE, the Investigator must notify the

IRB and Dexcom will notify the FDA within ten (10) working days of the original SAE notification.

If determined that the UADE presents an unreasonable risk to subjects, Dexcom will terminate all

investigations or parts of investigations presenting that risk as soon as possible, but not later than 5

working days after such determination is made and not later than 15 working days after Dexcom

first receives notice of the original SAE. Dexcom will not resume a terminated study without IRB

and FDA approval.

23.7 MDR Reportable Events/MDR Reporting

For purposes of this protocol, the CGM devices are either currently marketed or similar to devices

currently marketed in the US. Therefore, the sponsor will follow the required reporting regulations

if a MDR reportable event were to occur according to Sponsor SOP and FDA guidelines. (SOP-

300024 US MDR Reporting; Code of Federal Regulations Title 21 Part 803; Medical Device

Reporting; Draft Guidance for Industry and Food and Drug Administration Staff Medical Device

Reporting for Manufacturers: July 9, 2013, 19-21).

MDR reportable events are events that manufacturers become aware of that reasonably suggest one

of their marketed devices may have caused or contributed to a death or serious injury, or has

malfunctioned and the malfunction of the device would likely cause or contribute to a death or

serious injury if the malfunction were to recur (21 CFR 803.3).

24. ETHICAL CONSIDERATIONS

24.1 Informed Consent

Informed consent will be obtained in accordance with the Code of Federal Regulations (CFR) Title

21, Part 50. Subjects will be asked to sign state specific forms, such as Subject’s Bill of Rights, or

equivalent, (if applicable) and HIPAA authorization form, if not included in the site’s consent

template. Subjects will be provided the opportunity to review these documents prior to coming to

the clinical site. The Investigator or designee will explain the purpose and duration of the study,

the study procedures and subject requirements, and the potential risks and benefits. Study staff will

attempt to answer all questions the subject may have. Consenting process will be documented in

the subject’s source documents. A copy of the consent will be provided to the subject.

The study will be conducted in accordance with the Declaration of Helsinki (1964) including all

amendments up to and including the 1983 amendment per FDA’s Guidance for Industry:

Acceptance of Foreign Clinical Studies written in March, 2001.


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Subjects will receive a stipend for their participation in the study and a CGM system at the end of

Phase 1 if clinically warranted, subject was compliant with study protocol and requested by subject.

24.2 Institutional Review Board

The protocol, informed consent document, and subject training materials for this study will be

reviewed and approved by a duly constituted Institutional Review Board (IRB) before subjects are

screened.

The Investigator will ensure that all aspects of the IRB review are conducted in accordance with

current institutional, local, and national regulations. An IRB approval letter will be provided to the

Sponsor prior to study initiation. Protocol amendments must adhere to the same requirements as

the original protocol. The Investigator will submit all IRB-required reports and updates, including

any continuing review and/or final closeout reports. The Investigator will inform the IRB of any

reportable AEs as per the IRB reporting rules.

25. DATA COLLECTION This study will use electronic data capture (EDC). The Investigator or designee is responsible for

completing the CRFs. Good Documentation Practices principles will be required.

26. DEVICE ACCOUNTABILITY The Investigator(s) will store devices in a secure location at the clinical site. An accurate and current

accounting of the dispensing for the Dexcom and other device components will be maintained by

a member of the study site staff on the “Device Accountability Log”. All used and unused devices

must be returned to the Dexcom Clinical Affairs department (or accounted for if lost) upon

completion of enrollment or upon request of the Sponsor.

27. MONITORING

Monitoring will be conducted by trained and experienced Clinical Research Associates (CRAs) in

accordance with Dexcom’s standard operating procedures. CRAs will evaluate study conduct and

documentation on an ongoing basis. Assessment of site performance will be reviewed with Clinical

Affairs management to determine the level of monitoring required. All informed consent

documents will be source verified along with key data fields related to safety and performance

indicators. All CRF data will be collected via the EDC system designated for the study for analysis.

A risk-based monitoring plan will be developed consistent with the Food and Drug Administration

(FDA) Guidance for Industry: Oversight of Clinical Investigations—A Risk-based Approach to

Monitoring (August 2013). This approach focuses on critical study parameters and relies on a

combination of monitoring activities to oversee a study. Monitoring is separated into Central

(remote) monitoring and On-Site monitoring (site visits). Considerable focus is placed on real-time

centralized monitoring methods.

28. STUDY TERMINATION

Subject participation in the clinical study will be terminated following the last visit or when all AEs

have been resolved or considered ongoing but stable. Prior to this time, subjects may voluntarily

withdraw at any point in the study or the Investigator and/or Sponsor may determine that it is in the

best interest of the subject to be terminated from the study. Reasons for withdrawal of subject from

the study include, but are not limited, to the following:

a) In the opinion of the Investigator, the subject’s health or safety would be compromised by

continuing in the study


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b) In the opinion of the Investigator, it is in the subject’s best interest to discontinue participation

in the study

c) During the study, (female) subject becomes pregnant.

However, discontinuation of the study intervention (CGM) does not equate with discontinuation

from the study and every effort will be made to retain subjects in the study for the primary outcome

assessment, even if CGM is discontinued.

The clinical study in its entirety will be considered complete upon receipt of reports from study

monitoring activities, completion of site closeout visits, and issuance of a clinical study report. The

clinical study report will include all safety and efficacy data.

Any early termination of the study will be reported to the IRB.

29. INVESTIGATOR RESPONSIBILITIES

The Investigator’s signature(s) on this protocol confirms that the Investigator is familiar with all

sections of the protocol and agrees to conduct this study in accordance with the provisions of the

protocol and applicable regulations. The Investigator(s) must sign this protocol prior to

commencement of any study-related activities (e.g. screening).

The Investigator(s) are responsible for protecting the rights, safety, and welfare of subjects under

their care. The Investigator(s) are also responsible for obtaining IRB approval prior to study start

and the written informed consent of each subject before participation in this study. The informed

consent must comply with FDA regulations (21 CFR 50) and be approved by the IRB.

The Investigator(s) are responsible for ensuring completion of the CRFs per the study timelines

discussed in the site initiation visit and subsequent monitoring visits.

Dexcom and/or the IRB retain the right to disqualify an Investigational Site and remove all study

materials at any time. Specific instances, which may precipitate clinical site disqualification,

include but are not limited to:

a) Unsatisfactory subject enrollment with regard to quality and quantity.

b) Persistent non-compliance related to protocol procedures by the Investigator/Investigational

Center.

c) Inaccurate, incomplete, and/or untimely data recording on a recurrent basis.

d) The incidence and/or severity of adverse experiences in this or other studies indicating

inadequate oversight

e) Unsatisfactory accountability of study devices.

30. SPONSOR RESPONSIBILITIES

The Sponsor is responsible for selecting qualified Investigators and providing them with the

information needed to properly conduct the study. The Sponsor will ensure proper monitoring of

the study and that IRB approval has been obtained prior to the Investigator commencing study-

related activities. The Sponsor is also responsible for ensuring that the reviewing IRB(s) and FDA,

if applicable, are promptly informed of significant new information.

31. CONFIDENTIALITY OF RECORDS

All records and documents pertaining to this study will be retained for a period of no less than 2

years by Dexcom, Inc. and will be available for inspection by FDA or other regulatory agencies at

any time. All records containing personal identification or information that identifies a study


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subject will be handled confidentially within the law. These records will be coded and kept in

locked files. No individual identities will be used in any reports or publications resulting from this

study.

Neither the site nor subjects will disclose, share, or use any information gathered during the course

of the clinical study. All information about the study, including the study product and study

procedures, is confidential. Any publication about the products or the study by print or electronic

format (e.g. blogging) is strictly prohibited.


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32. REFERENCES

1. Gale E. Declassifying diabetes. Diabetologia. 2006;49:1989-1995.

2. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates

and general information on diabetes and prediabetes in the United States. 2011. Available at:

http://www.cdc.gov/diabetes/pubs/factsheet11.htm.

3. Zimmet P, et al. Preventing type 2 diabetes and the dysmetabolic syndrome in the real world:

a realistic view. Diábêt Med. 2003;20:693-702.

4. The Diabetes Control and Complications Trial Research Group. The effect of intensive

treatment of diabetes on the development and progression of long-term complications of

insulin-dependent diabetes mellitus. N Eng J Med. 1993;329:977-986.

5. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents progression of

diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes

mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117.

6. The Diabetes Control and Complications Research Group. –The DCCT Research Group: Effect

of intensive diabetes treatment on the development and progression of long-term complications

in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications

Trial. J Ped 1994; 125:177-188.

7. Bolinder J, Ungerstedt U, Hagstrom-Toft E, Arner P. Self-monitoring of blood glucose in Type

1 diabetic patients: comparison with continuous micro dialysis measurements of glucose in

subcutaneous adipose tissue during ordinary life conditions. Diabetes Care. 1997; 20:64-70.

8. Bode, Bruce W., et al. Glycemic Characteristics in Continuously Monitored Patients with Type

1 and Type 2 Diabetes. Diabetes Care. 2005: 28: 2361-2366.

9. Pickup J. Are insulin pumps underutilized in type 1 diabetes? Yes. Diabetes Care.

2006;29:1449-1452.

10. Raccah, D., et al. Incremental Value of Continuous Glucose Monitoring When Starting Pump

Therapy in Patients with Poorly Controlled Type 1 Diabetes. Diabetes Care. 2009, 32:12:

2245-2250.

11. The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group.

Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Eng J Med.

2008;359:1464-1476.

12. Battelino T, et al. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes.

Diabetes Care. 2011;34:795-800.

13. Riveline J, et al. Assessment of patient-led or physician-led continuous glucose monitoring in

patients with poorly controlled type 1 diabetes using basal-bolus insulin regimens. Diabetes

Care. 2012;35:965-971.

14. Garg S, et al. Use of continuous glucose monitoring in subjects with type 1 diabetes on multiple

daily injections versus continuous subcutaneous insulin infusion therapy. Diabetes Care.

2011;34:574-579.

15. Rodbard D, et al. Responses to continuous glucose monitoring in subjects with type 1 diabetes

using continuous subcutaneous insulin infusion or multiple daily injections. Diabetes Technol

Ther. 2009;11:757-765.

16. Deiss D, et al. Improved glycemic control in poorly controlled patients with type 1 diabetes

using real-time continuous glucose monitoring. Diabetes Care. 2006;29:2730-2732.


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17. Langendam M, et al. Continuous glucose monitoring systems for type 1 diabetes mellitus

(review). Cochrane Database of Systematic Reviews. 2012;1.

a. doi: 10.1002/14651858.CD008101.pub2.

18. Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence

of distress symptoms: a comparison of the SF-36 Mental Health subscale and the WHO-Five

Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 8591.

19. Szende et al. Self-reported population health: an international perspective based on EQ-5D.

2014. XV. 196p.

20. Polonsky WH, Fisher L, Earles J, Dudl RJ, Lees J, Mullan J, Jackson RA (2005).Assessing

psychosocial distress in diabetes: Development of the Diabetes Distress Scale. Diabetes Care,

28, 626-631.

21. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J: Fear of hypoglycemia:

quantification, validation, and utilization. Diabetes Care 10:617-621, 1987.

22. Polonsky WH, Hypoglycemia Confidence Scale, Behavioral Diabetes Institute.

23. Polonsky WH, Bolus Insulin Questionnaire, Behavioral Diabetes Institute.

24. Huizinga, MM, et al, “Development and Validation of the Diabetes Numeracy Test (DNT)”

Diabetes Numeracy Test; copyright 2007 by Vanderbilt University.

25. Clarke, WL, Cox DJ, Gonder-Frederick, LA, Julian D, Schlundt, D, Polonsky WH; Reduced

Awareness of Hypoglycemia in Adults with IDDM. Diabetes Care 18:4 517-522, 1995.

26. Polonsky, WH; CGM Expectations Questionnaire, Behavioral Diabetes Institute.

27. Polonsky WH, Hessler D (2013). What are the quality of life-related benefits and losses

associated with real-time continuous glucose monitoring? A survey of current users. Diabetes

Technol Ther, 15, 295-301.

28. Tansy M, et al, Satisfaction with continuous glucose monitoring in adults and youths with Type

1 diabetes. Diabet Med 2011 Sep: 28(9): 1118-22 doi: 10. 1111/j. 1464-5491. 2011. 03368.x.

29. National Glycohaemoglobin Standardization Program (NGSP). Harmonizing hemoglobin A1C

testing. Division of Laboratory Sciences and the Centers for Disease Control and Prevention.

2010. 22 Jun 2011. http://www.ngsp.org/index.asp.

http://www.ngsp.org/index.asp

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33. APPENDICES

Appendix A: Informed Consent

Appendix B: Study Flowchart

Appendix C: Clinician Guidelines: General Diabetes Education

Appendix D: Clinician Guidelines for Follow-Up Visits

Appendix E: Visit Flowchart

Appendix F: Diabetes Management Guidelines Using CGM

Appendix G: Patient Reported Outcome (PRO) Measures

Appendix H: Test and Exam Table

Appendix I: Sample CGM Information Guide

Appendix J: OmniPod Guidance Documents

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Appendix A: Informed Consent

ICF_T1DM_20May15

.docx

ICF_T2DM_20May15

.doc

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Appendix B: Overall Study Flowchart

Appendix B_Overall

Study Flowchart_v3.docx

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Appendix C: Clinician Guidelines: General Diabetes Education

Appendix

C_Clinician Guidelines_v3.docx

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Appendix D: Clinician Guidelines for Follow-Up Visits

Appendix

D_Dexcom PTL901148_v3.docx

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Appendix E: Visit Flowchart

Appendix E_Visit

Flowchart_rev3.docx

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Appendix F: Diabetes Management Guidelines Using CGM

Diabetes

Management Guidelines Using CGM_v3.0.docx

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Appendix G: Patient Reported Outcome (PRO) Measures

Appendix

G_BolusInsulinQuestionnaire_v3.0.docx

Appendix G_Care

Management Time Form_v3.docx

Appendix G_CGM

Attitudes_v3.0.docx

Appendix G_CGM

Expectations_v3.0.docx

Appendix G_CGM

Satisfaction_v3.0.docx

Appendix G_Clarke

Hypo_v3.0.docx

Appendix

G_DDS_v3.0.docx

Appendix

G_DNT5_v3.0.docx

Appendix

G_EQ_5D_5L_v3.pdf

Appendix G_Health

Service Form_v3.docx

Appendix

G_HFS-W_v3.0.docx

Appendix G_Hypo

Confidence_v3.0.docx

Appendix

G_WHO-5_v3.0.docx

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-

Appendix H: Test and Exam Table

Appendix

H_Test&Exam Table_v3.docx

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Appendix I: Sample CGM Information Guide This is a sample of CGM information and training that may be used by clinicians at the study site:

Appendix I_Joslin's Guide to Real Time Continuous Glucose Monitoring.pdf

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Appendix J: OmniPod Guidance Documents

Appendix J_OmniPod Training Checklist.pdf

Ten Tips for Better Podding.pdf